Method of inhibiting gastric acid secretion with 5-substituted-3-aminochromane

ABSTRACT

The present invention provides a method of inhibiting gastric acid secretion in mammals by administering a 5-HT1A agonist compound or a pharmaceutically acceptable salt thereof.

This application is a division of prior application Ser. No. 08/387,492,filed Feb. 13, 1995, which is a division of prior application Ser. No.08/219,157, filed Mar. 29, 1994, now U.S. Pat. No. 5,457,120, which is adivision of prior application Ser. No. 08/068,723, filed May 26, 1993,now U.S. Pat. No. 5,340,838, which is a division of prior applicationSer. No. 07/898,991, filed Jun. 15, 1992, now U.S. Pat. No. 5,258,379,which is a division of prior application Ser. No. 07/707,357, filed May29, 1991, now U.S. Pat. No. 5,158,956, which is a continuation-in-partof application Ser. No. 07/519,388, filed May 4, 1990, now U.S. Pat. No.5,096,908.

BACKGROUND OF THE INVENTION

Over the last several years it has become apparent that serotonin(5-hydroxytryptamine; 5-HT) is associated directly or indirectly with anumber of physiological phenomena, including appetite, memory,thermoregulation, sleep, sexual behavior, anxiety, depression, andhallucinogenic behavior [Glennon, R. A., J. Med. Chem. 30, 1 (1987)].

5-HT receptors have been identified in the central nervous system (CNS;brain and spinal cord) and in peripheral tissues including thegastrointestinal tract, lung, heart, blood vessels, and various othersmooth muscle tissues.

It has been recognized that there are multiple types of 5-HT receptors.These receptors have been classified as 5-HT1, 5-HT2, and 5-HT3 with atleast the 5-HT1 receptor being further divided into sub-classesidentified as 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D.

In the CNS, 5-HT receptors are located post-synaptically, on neuronsthat receive serotonergic input, and presynaptically on 5-HT releasingneurons. The presynaptic receptors are believed to function to sense theconcentration of 5-HT in the synaptic cleft and modulate the furtherrelease of 5-HT accordingly.

Generally, an "agonist" is a chemical compound that mimics the action ofthe endogenous neurotransmitter at receptors.

Direct-acting serotonin agonists are chemical substances that bind toand mimic the action of serotonin on serotonin receptors.

Indirect-acting serotonin agonists are chemical substances that increasethe concentration of serotonin in the synaptic cleft. Indirect serotoninagonists include inhibitors of a serotonin specific uptake carrier,agents that release serotonin from storage granules, agents (serotoninprecursors) that increase serotonin formation, and monoamine oxidase(MAO) inhibitors that block serotonin degradation and thereby increasethe amount of serotonin available.

The primary focus of research efforts surrounding the biochemistry andphysiology of serotonin and serotonin agonists has been directed towardthe CNS, generally, and the brain in particular.

Serotonin is known to have a number of actions in the gastrointestinaltract. It is known that the intravenous infusion in humans of 5-HT or5-HTP (5-hydroxytryptophane) inhibits the volume and acidity of bothspontaneous and histamine induced gastric secretion while simultaneouslyincreasing the production of mucus [Handbook of ExperimentalPharmacology, Vol XIX, "5-Hydroxytryptamine and RelatedIndolealkylamines" Erspamer, V., sub-ed., Springer-Verlog, New York,1966, pp. 329-335]. It is not known whether binding at one or somecombination of 5-HT receptor sites is required to effect this inhibitionresponse or which receptor(s) are involved.

It is known that 5-HT receptors in smooth muscle of the gastrointestinaltract mediate contraction of this tissue. The rat fundus and guinea pigileum are widely used for in vitro studies of 5-HT agonists andantagonists. The enterochromaffin cells of the gastrointestinal tractare the major site of 5-HT production in the body. Although 5-HT and5-HT receptors are known to be present in the gastrointestinal tract,their physiological roles are not clear.

It has been discovered that direct acting 5-HT1A agonists inhibit thesecretion of gastric acid. These agents are, therefore, useful in thetreatment of conditions where inhibition of gastric acid secretion isnecessary or desirable such as gastric and peptic ulceration.

It is a primary object of the present invention to provide a method ofinhibiting gastric acid secretion by administering to a mammal in needof such treatment a compound having direct-acting 5-HT1A receptoragonist activity.

Other objects, features and advantages of the present invention willbecome apparent to one skilled in the art from the subsequentdescription and the appended claims.

SUMMARY OF THE INVENTION

The present invention provides a method of inhibiting gastric acidsecretion in mammals comprising administering to a mammal in need ofgastric acid secretion inhibition an effective dose of a direct acting5-HT1A receptor agonist or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The method of this invention is practiced by administering to a mammal adirect acting 5-HT1A agonist or a pharmaceutically acceptable saltthereof, preferably in a pharmaceutical formulation.

The phrase "direct acting 5-HT1A agonist" as used in this specificationand these claims means a non-endogenous chemical compound andincludes: 1) synthetic chemical compounds (ligands) that mimic theaction of serotonin on 5-HT1A receptors by directly activating thesereceptors; and 2) partial agonists, which are synthetic chemicalcompounds (ligands) that mimic the action of serotonin on 5-HT1Areceptors by directly activating these receptors but produce a smallermaximal effect than do other ligands that act on the same receptor.These compounds may have activity at other receptors but must have somecomponent of 5-HT1A agonist activity.

Compounds within both of these groups of ligands must possess bothaffinity for the 5-HT1A receptor site and efficacy in that gastric acidsecretion is lowered. The affinity and efficacy may be at CNS receptors,peripheral receptors or both or on acid secretory cell receptors; thatis, the compounds within either group may be able to pass theblood/brain barrier, but this is not a requirement.

The 5-HT1A agonists contemplated as within the scope of the presentinvention are those having an apparent binding affinity, typicallyreported as K_(i) value, of from about 0.01 nM to about 5000 nMcalculated from inhibitor IC₅₀ values using the equation K_(i) =IC₅₀/[1+(L/K_(d))] where L is the radioligand concentration and K_(d) is thedissociation constant of the ligand-receptor complex determined bysaturation studies or from the inhibition by the cold ligand for its ownbinding.

Procedures for performing binding assays to determine 5-HT1A agonistactivity are known to those skilled in the art. For example, suchtechniques are described in Wong et al., Life Sciences, 46, 231-235(1990) and references cited therein. Similarly, the relationship betweenapparent binding affinity K_(i) as a function of inhibitor IC₅₀ values,radioligand concentration and dissociation of the ligand-receptorcomplex as described in the above formula is also known to those skilledin the art. For example, see Cheng et. al., Biochemical Pharmacology,22, 3099-3108 (1973); and Taylor et. al., Life Sciences, 41, 1961-1969(1987).

The method of the present invention is useful in the treatment andprevention of disorders of the gastrointestinal tract associated withunnecessary or undesirable gastric acid secretion including peptic ulcergastric and duodenal ulcers, gastritis, gastroesophogeal reflux disease,gastric dispepsia, and Zollinger-Ellison syndrome.

The following classes of direct acting 5-HT1A agonists have beenreported and are useful in the method of the present invention: 1)2-amino-1,2,3,4-tetrahydronaphthalenes and 3-amino chromanes; 2)4-amino-1,3,4,5-tetrahydrobenz-[c,d]indoles; 3) nonendogenous indoles;4) aryloxy propanolamines; 5) benzodioxanes; 6) phenylcyclopropylamines;7) N-arylpiperazines; and 8) piperidinylmethyl tetrahydroisoquinolines.Each of these classes will now be described in further detail.

2-Amino-1,2,3,4-Tetrahydronaphthalenes and 3-Amino Chromanes

The first class comprises8-substituted-2-amino-1,2,3,4-tetrahydronaphthalenes, and thecorresponding 5-substituted-3-amino chromanes, having 5-HT1A agonistactivity, and pharmaceutically acceptable acid addition salts thereof.The 2-amino-1,2,3,4-tetrahydronaphthalenes are more widely known with8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) asperhaps the best known example. Further tetrahydronaphthalene analoguesinclude the 8-methoxy derivative and 2-mono-(C₁ -C₄)alkylamino and di(C₁-C₄)alkylamino derivatives. These compounds and others are described inand prepared according to procedures in Arvidsson, L. E. et al., J. Med.Chem., 27, 45 (1984); Naiman, N. et al., J. Med. Chem., 32, 253 (1989);EPA 334 538, U.S. Pat. No. 4,845,221; and EPA 272 534A which are allincorporated herein by reference in their entirety. Specificillustrative compounds include:

8-methoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalene

8-methoxy-2-(ethylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(ethylamino)-1,2,3,4-tetrahydronaphthalene

(±) 8-methoxy-2-(propylamino)-1,2,3,4-tetrahydronaphthalene

(+) 8-methoxy-2-(propylamino)-1,2,3,4-tetrahydronaphthalene

(-) 8-methoxy-2-(propylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(propylamino)-1,2,3,4-tetrahydronaphthalene

8-methoxy-2-(butylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(butylamino)-1,2,3,4-tetrahydronaphthalene

8-methoxy-2-(isopropylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(isopropylamino)-1,2,3,4-tetrahydronaphthalene

8-methoxy-2-(dimethylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(dimethylamino)-1,2,3,4-tetrahydronaphthalene

8-methoxy-2-(diethylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(diethylamino)-1,2,3,4-tetrahydronaphthalene

8-methoxy-2-(ethylpropylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2(ethylpropylamino)-1,2,3,4-tetrahydronaphthalene

(±) 8-methoxy-2-(dipropylamino)-1,2,3,4-tetrahydronaphthalene

(±) 8-methoxy-2-(dipropylamino)-1,2,3,4-tetrahydronaphthalene

(-) 8-methoxy-2-(dipropylamino)-1,2,3,4-tetrahydronaphthalene

(±) 8-OH-DPAT

(+) 8-OH-DPAT

(-) 8-OH-DPAT

8-methoxy-2-(propylbutylamino)-1,2,3,4-tetrahydronaphthalene

8-hydroxy-2-(propylbutylamino)-1,2,3,4-tetrahydronaphthalene

Additional ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes and3-amino chromanes having 5-HT1A agonist activity, are those having theformula ##STR1## in which R is C₁ -C₄ alkyl, allyl, orcyclopropylmethyl; R¹ is hydrogen, C₁ -C₄ alkyl, allyl,cyclopropylmethyl, or aryl(C₁ -C₄ -alkyl);

R² is hydrogen or methyl;

X is --CH₂ -- or --O--;

R³ is C₁ -C₈ alkyl, aryl, substituted aryl, aryl(C₁ -C₄ -alkyl),substituted aryl(C₁ -C₄ alkyl), or C₅ -C₇ cycloalkyl;

n is 0, 1, or 2;

and pharmaceutically acceptable acid addition salts thereof.

In the above formula, the term "C₁ -C₄ alkyl" means a straight orbranched alkyl chain having from one to four carbon atoms. Such C₁ -C₄alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, and t-butyl.

The term "aryl" means an aromatic structure whether carbocyclic orheterocyclic. Examples of such ring structures are phenyl, naphthyl,furyl, pyridyl, thienyl, and the like.

The aryl group may contain a ring substituent. Examples of typical ringsubstituents are C₁ -C₃ alkyl, C₁ -C₃ alkoxy, halo, hydroxy, C₁ -C₃thioalkyl, trifluoromethyl, and the like.

In the foregoing, the term "C₁ -C₃ alkoxy" means any of methoxy, ethoxy,n-propoxy, and isopropoxy; the term "halo" means any of fluoro, chloro,bromo, and iodo; and the term "C₁ -C₃ thioalkyl" means any ofmethylthio, ethylthio, n-propylthio, and isopropylthio.

Among the 5-HT1A agonist compounds included in this class as describedabove, including those compounds described in references that have beenincorporated by reference, certain of these compounds are preferred. Thepreferred compounds are those having the Formula ID ##STR2## where R isC₁ -C₄ alkyl, allyl, or (C₃ -C₅ cycloalkyl)methyl;

R¹ is hydrogen, C₁ -C₄ alkyl; allyl; (C₃ -C₅ cycloalkyl)-methyl, oraryl(C₁ -C₄ -alkyl);

R² is hydrogen or methyl;

X⁴ is OH, C₁ -C₆ alkoxy, halo COOR³ or S(O)_(n) R³ ;

R³ is C₁ -C₈ alkyl, aryl, substituted aryl, aryl(C₁ -C₄ -alkyl),substituted aryl(C₁ -C₄ alkyl); or C₅ -C₇ cycloalkyl; or

R and R¹ together with the nitrogen atom form a group ##STR3## where Ais 3-trifluoromethylphenyl, 3-halophenyl,

2-pyrimidinyl, halopyrimidin-2-yl,

2-pyrazinyl or halo-2-pyrazinyl;

n is 0, 1, or 2; or a pharmaceutically acceptable acid addition saltthereof.

More preferably, R² is hydrogen; R and R¹ preferably are both C₁ -C₄alkyl, and, more preferably, both are n-propyl. Also, n preferably iszero; R³ preferably is C₁ -C₈ alkyl, substituted aryl, or substitutedaryl(C₁ -C₄ -alkyl), and, most preferably, methyl.

The compounds of Formula I and other2-amino-1,2,3,4-tetrahydronaphthalenes within class one possess anasymmetric carbon represented by the carbon atom labeled with anasterisk in the following formula: ##STR4##

As such, each of the compounds exists as its individual d- andl-stereoisomers as well as the racemic mixture of such isomers.Accordingly, the compounds of the present invention include not only thedl-racemates but also their respective optically active d- andl-isomers.

In addition, when R² is methyl, a second asymmetric carbon, at the R²substituent, is present, giving rise to a further class ofstereoisomers.

As mentioned hereinabove, useful compounds for practicing the method ofthe present invention includes pharmaceutically acceptable acid additionsalts of the compounds defined by the above Formula I and other2-amino-1,2,3,4-tetrahydronaphthalenes within class one. Since thesecompounds are amines, they are basic in nature and accordingly reactwith any of a number of inorganic and organic acids to formpharmaceutically acceptable acid addition salts. Since the free aminesof these compounds are typically oils at room temperature, it ispreferable to convert the free amines to their correspondingpharmaceutically acceptable acid addition salts for ease of handling andadministration, since the latter are routinely solid at roomtemperature. Acids commonly employed to form such salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexynel,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene2-sulfonate, mandelate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid.

In addition, some of these salts may form solvates with water or organicsolvents such as ethanol. Such solvates also are included within thescope of this invention.

The following compounds further illustrate compounds contemplated withinthe scope of Formula I:

1-Methyl-2-(di-n-propylamino)-8-methylthio-1,2,3,4-tetrahydronaphthalene;

2-Ethylamino-8-ethylthio-1,2,3,4-tetrahydronaphthalene;

2-(N-Methyl-N-benzylamino)-8-methylthio-1,2,3,4-tetrahydronaphthalene;

2-Diallylamino-8-ethylthio-1,2,3,4-tetrahydronaphthalene;

1-Methyl-2-diethylamino-8-ethylsulfinyl-1,2,3,4-tetrahydronaphthalene;

1-Methyl-2-(di-n-propylamino)-8-ethanesulfonyl-1,2,3,4-tetrahydronaphthalene;

1-Methyl-2-benzylmethylamino-8-methylthio-1,2,3,4-tetrahydronaphthalene;

1-Methyl-2-(di-n-propylamino)-8-n-propylthio-1,2,3,4-tetrahydronaphthalene;

2-Dimethylamino-8-benzenesulfonyl-1,2,3,4-tetrahydronaphthalene;

2-(Di-cyclopropylmethylamino)-8-(p-toluenesulfonyl)-1,2,3,4-tetrahydronaphthalene;

2-(Di-n-propylamino)-8-(p-chlorobenzenesulfonyl)thio-1,2,3,4-tetrahydronaphthalene;

2-Ethylamino-8-n-propylthio-1,2,3,4-tetrahydronaphthalene;

2-n-Butylamino-8-ethylthio-1,2,3,4-tetrahydronaphthalene;

2-(Di-n-propylamino)-8-n-octylthio-1,2,3,4-tetrahydronaphthalene;

2-(Di-n-propylamino)-8-methylthio-1,2,3,4-tetrahydronaphthalene;

3-(Di-n-propylamino)-5-methylthio-chromane; and the like.

The compounds of Formula I may be prepared by procedures well known tothose of ordinary skill in the art. The compounds in which X is --CH₂preferably are synthesized by preparation of an 8-bromo-2-tetralone. The8-bromo-2-tetralone then is reductively aminated with the desired amineafter which the bromo substituent is replaced with the desired thiosubstituent.

Schemes for these reactions are as follows:

A. Syntheses of 8-Bromo-2-tetralone and 8-Bromo-1-methyl-2-tetralone##STR5## C. Replacement of Bromo Ring Substituent Via Lithiation##STR6##

As depicted above, the 8-bromo-2-tetralones represent the intermediatewhich, when reductively aminated, lithiated, and treated with theappropriate disulfide, result in compounds of Formula I and/or compoundsuseful as intermediates to the preparation of compounds of Formula I.

The tetralones are available by any of a wide range of recognizedmethods. For example, they can be produced by a Friedel-Crafts reactionof an appropriately ring-substituted phenylacetyl chloride with ethylenein the presence of aluminum chloride.

When R² in the compounds of Formula I is methyl, the methyl-substituted8-bromo-2-tetralone can be prepared from the corresponding unsubstituted8-bromo-2-tetralone. The 8-bromo-2-tetralone first is treated withpyrrolidine to produce the corresponding1,2-dihydro-3-pyrrolidinyl-naphthalene. The latter, upon treatment withmethyl iodide and acid hydrolysis, gives the desired8-bromo-1-methyl-2-tetralone.

The tetralone, once formed, can, by simple reductive amination using theselected amine, be converted to a2-amino-8-bromo-1,2,3,4-tetrahydronaphthalene useful as an intermediateto a compound of Formula I. The tetralone is first reacted with theamine to form the corresponding enamine after which the enamine isreduced with sodium borohydride or sodium cyanoborohydride to thetetrahydronaphthalene.

The 2-amino-8-bromo-1,2,3,4-tetrahydronaphthalene is used to producecompounds of Formula I by formation of a lithium intermediate via alithiation reaction using an alkyl lithium, preferably n-butyl-lithium.The reactive lithium intermediate then is treated with an appropriatedisulfide to produce the 8-thio compounds of Formula I.

Alternatively, the 8-bromo-2-tetralone can first be protected and thenlithiated and treated with the appropriate disulfide. The resulting8-thio-2-tetralone, after deprotection, can then be reductively aminatedto a compound of Formula I.

The compounds of Formula I in which X is oxygen are available byreductive amination and bromo replacement as in the foregoing, but using5-bromo-3-chromanone. This molecule can be produced by a sequence ofreactions beginning with m-bromophenol. The detailed reaction sequenceis provided in the Examples following. Briefly, m-bromophenol is treatedwith allyl bromide in the presence of potassium carbonate to produceallyl 3-bromophenyl ether. The ether is converted to2-allyl-3-bromophenol upon heating it in the presence ofN,N-dimethylaniline. The phenol, upon reaction with ethyl chloroacetate,is converted to the ethyl ester of2-allyl-3-(carboxymethoxy)bromobenzene. Upon oxidation using ozonefollowed by reductive work up, the allyl group is converted to aformylmethyl substituent which is then further oxidized using Jones'Reagent to the carboxymethyl substituent, the resulting product beingthe ethyl ester of (2-carboxymethyl-3-bromo)phenoxyacetic acid. Thepartial ester is converted to the diethyl ester using ethanol andgaseous hydrogen chloride. In the presence of potassium t-butoxide, thediester is cyclized to a mixture of4-ethoxycarbonyl-5-bromo-3-chromanone and2-ethoxycarbonyl-5-bromo-3-chromanone. Upon heating the latter in thepresence of acid, it is converted to 5-bromo-3-chromanone.

The 8-thio compounds, upon treatment with sodium metaperiodate, can beoxidized to the corresponding 8-sulfinyl compounds. Additionalcompounds, the 8-sulfonyl compounds, are available by treatment of the8-sulfinyl compounds with m-chloroperbenzoic acid.

The optically active isomers of the racemates of the invention are alsoconsidered within the scope of Formula I. Such optically active isomersmay be prepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theseresolutions can can typically be carried out in the presence of aresolving agent, by chromatography or by repeated crystallization.Procedures for separating racemates into their individual isomers can befound in references such as Jacques et. al, Enantiomers, Racemates andResolutions, (John Wiley and Sons, New York 1981). This referencedescribes procedures used to find a resolving agent using the trial anderror method. It also describes how to carry out a resolution afterfinding a resolving agent.

As described above, the compounds of Formula I generally andconveniently are produced via an 8-substituted-2-tetralone or a5-substituted-3-chromanone. Either of these intermediates may bereductively alkylated with an optically active α-phenethylamine afterwhich the resulting mixture of diastereomers is separated by recognizedmethodology, such as chromatography. Cleavage of the α-phenethyl moietyproduces a correspondingly substituted, optically active2-amino-1,2,3,4-tetrahydronaphthalene or 3-aminochromane.

The conditions necessary for removing the phenethyl moiety arerelatively severe and can cleave substituent groups on the core tetralinor chromane molecule. The cleavage of the phenethyl moiety can becarried out in a much more facile and efficient manner requiring onlymild cleavage conditions when the particular α-phenethylamine which isused is p-nitro-α-phenethylamine.

Cleavage of the p-nitro-α-phenethyl moiety is achieved by reduction ofthe p-nitro group followed by acid-catalyzed solvolysis of the resultingp-amino-α-phenethyl moiety. Reduction of the nitro group can beaccomplished by a wide range of reducing agents including, for example,titanium trichloride, or zinc/acetic acid, or by catalytic hydrogenationparticularly using sulfided palladium on carbon as catalyst. Solvolyticcleavage takes place when the monohydrochloride (or other monobasicsalt) of the reduction product is treated with water or an alcohol atroom temperature or, in some instances, at elevated temperatures. Aparticularly convenient condition for removing the p-nitro-α-phenethylmoiety is hydrogenation of the amine monohydrochloride in methanol overa platinum catalyst.

Compounds highly useful as intermediates to the compounds of Formula Iare the corresponding 8-bromotetralins. It has been discovered that the8-bromo compounds in their optically active form are not available usingroutine methodology. The optical antipodes of 8-bromo-2-aminotetralinmay be prepared using methods employing p-nitro-α-phenethylaminedescribed above. These compounds may then be converted to compounds IBand IC using alkylating procedures known to those skilled in the art.##STR7##

In the foregoing, R is hydrogen, C₁ -C₄ alkyl, allyl, orcyclopropylmethyl; and

R¹ is hydrogen, C₁ -C₄ alkyl, allyl, cyclopropylmethyl, or aryl(C₁ -C₄-alkyl). The compounds employed as initial starting materials in thesynthesis of the compounds of this invention are well known and readilysynthesized by standard procedures commonly employed by those ofordinary skill in the art.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a 1,2,3,4-tetrahydronaphthalene or chromane of Formula Iwith an equimolar or excess amount of acid. The reactants are generallycombined in a mutual solvent such as diethyl ether or benzene, and thesalt normally precipitates out of solution within about one hour to 10days, and can be isolated by filtration.

The following preparation Examples further illustrate the compounds ofFormula I and methods for their synthesis. These Examples are notintended to be limiting to the scope of the invention in any respect andshould not be so construed.

Unless otherwise noted, the NMR data appearing in the following examplesrefers to the free bases of the subject compounds.

Preparation Example 1 Preparation of2-Di-n-propylamino-8-thiomethyl-1,2,3,4-tetrahydronaphthalene.

A. 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene.

To a solution of 8-bromo-2-tetralone (3.0 gm, 13.3 mMol) in toluene (25mL) were added di-n-propylamine (3.5 mL, 26 mMol) and p-toluenesulfonicacid (100 mg, 0.52 mMol). The reaction was heated to reflux, water beingcollected in a Dean-Stark trap. After four hours the reaction wasconcentrated in vacuo to give8-bromo-2-dipropylamino-3,4-dihydronaphthalene as a dark liquid whichwas immediately dissolved in methanol (50 mL) and acetic acid (5 mL). Tothis solution was then added sodium borohydride (2.0 gm, 52.9 mMol), andthe mixture was stirred 18 hours at room temperature.

The reaction mixture was then diluted with 6N hydrochloric acid, stirredone hour at room temperature and then concentrated in vacuo. The residuewas dissolved in water and washed once with diethyl ether. The remainingaqueous phase was made strongly basic with ammonium hydroxide andextracted well with dichloromethane. These organics were combined, dried(Na₂ SO₄) and concentrated in vacuo to give the crude title compound asa dark oil. Purification by chromatography on basic alumina(dichloromethane) gave the product as a colorless oil. The hydrochloridesalt was formed. Recrystallization (ethanol/diethyl ether) gave acolorless, crystalline solid (1.30 gm, 28%, m.p.=155° C.).

Alternatively, to the 8-bromo-2-dipropylamino-3,4-dihydronaphthalene(44.4 mMol) in tetrahydrofuran (100 ml) was added sodiumcyano-borohydride (2.86 gm, 45.5 mMol) and the suspension was saturatedwith hydrogen chloride. After stirring for four hours the reactionmixture was poured into 15% aqueous sodium hydroxide (500 ml) and wasstirred an additional two hours. This mixture was extracted with diethylether, and the ether extracts were combined, washed with water, washedwith saturated aqueous sodium chloride, dried (Na₂ SO₄) and concentratedin vacuo to give the crude title compound as a light orange oil.Purification by basic alumina chromatography (dichloromethane) gave theproduct as a light yellow oil (7.8 gm, 57%).

Analysis: Calculated for C₁₆ H₂₄ NBr.HCl: Theory: C, 55.42; H, 7.27; N,4.04; Found: C, 55.53; H, 7.22; N, 3.84.

MS: 311(17), 309(16), 282(100), 280(100), 211(30), 209(32), 130(92),129(54), 128(40), 115(32), 72(43).

NMR (CDCl₃): 7.6-7.25(m, 1H), 7.2-6.9(m, 2H), 3.35-2.80(m, 5H),2.80-2.40(m, 4H), 2.40-1.20(m, 6H), 1.19-0.80 (t, J=7 Hz, 6H ).

B. 2-Di-n-propylamino-8-methylthio-1,2,3,4-tetrahydronaphthalene

To a solution of8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (600 mg, 1.93mMol) in tetrahydrofuran (20 mL) at -78° C. was added a solution ofn-butyllithium in hexane (1.6M, 1.9 mL, 3.04 mMol). The solution wasstirred at -78° C. for one hour, forming a light orange solution.Dimethyl disulfide (0.24 mL, 3.00 mMol) was added, and the reactionmixture was allowed to warm gradually to room temperature. The colorlesssolution was diluted with water and extracted with dichloromethane. Thedichloromethane extracts were combined, dried (Na₂ SO₄), andconcentrated in vacuo to give the crude product as a light yellow oil.Purification by flash chromatography (3% methanol in dichloromethane+tr.NH₄ OH) gave the product as a colorless, viscous oil (430 mg, 80%). Thehydrochloride salt was formed. Recrystallization (ethanol/diethyl ether)gave a colorless, crystalline solid (m.p.=185° C.).

Analysis: Calculated for C₁₇ H₂₇ NS.HCl: Theory: C, 65.04; H, 8.99; N,4.46; Found: C, 65.25; H, 9.13; N, 4.47.

MS: 277(31), 251(10), 250(29), 248(100), 177(90), 132(15), 130(69),128(50), 127(48).

NMR (CDCl₃): 7.13-6.68(m, 3H), 3.20-2.68(m, 4H), 2.62-2.33(m, 4H),2.44(s, 3H), 2.12-1.81(m, 1H), 1.72-1.20(m, 6H), 1.00-0.86 (6, J=7 Hz,6H).

Preparation Example 2 Preparation of2-Di-n-propylamino-8-thioethyl-1,2,3,4-tetrahydronaphthalene

Using the procedure described in Example 1,8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (930 mg, 3.0mMol) was reacted with diethyl disulfide (0.40 mL, 3.3 mMol) to give thecrude title compound as a light yellow oil. Purification by flashchromatography (33% diethyl ether in hexane+tr. NH₄ OH) gave the desiredproduct as a colorless oil (650 mg, 74%). The fumarate salt was formed.Recrystallization (ethanol/diethyl ether) gave a colorless, crystallinesolid (m.p.=105°-107° C.).

Analysis: Calculated for C₁₈ H₂₉ NS.C₄ H₄ O₄ : Theory: C, 62.09; H,8.28; N, 2.83; Found: C, 61.87; H, 8.42; N, 3.11.

MS: 292(3), 290(16), 281(2), 280(8), 278(29), 250(18), 249(11), 207(5),134(26), 119(10), 74(56), 59(88), 44(78).

NMR (CDCl₃): 7.08-6.72(m, 3H), 3.24-2.70(m, 6H), 2.70-2.36(m, 4H),2.16-1.86(m, 1H), 1.76-1.20(m, 9H), 1.08-0.76(t, J=7 Hz, 6H).

Preparation Example 3 Preparation of2-Di-n-propylamino-8-thiophenyl-1,2,3,4-tetrahydronaphthalene

Using the procedure described in Example 1,8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (930 mg, 3.0mMol) was reacted with diphenyl disulfide (720 mg, 3.3 mMol) to give thetitle compound as a colorless oil. The fumarate salt was formed.Recrystallization (acetone/diethyl ether) gave colorless crystals (270mg, 20%, m.p.=133°-135° C.)

Analysis: Calculated for C₂₂ H₂₉ NS.C₄ H₄ O₄ : Theory: C, 68.54; H,7.30; N, 3.07; Found: C, 68.37; H, 7.24; N, 3.09.

MS: 339(16), 311(7), 310(25), 309(100), 239(24), 237(22), 161(28),130(35), 129(40), 128(35).

NMR (CDCl₃): 7.18(s, 5H), 7.04-6.80(m, 3H), 3.08-2.72(m, 4H),2.32-2.27(m, 4H), 2.11-1.63(m, 1H), 1.63-1.18(m, 6H), 1.04-0.68(t, J=7Hz, 3H).

Preparation Example 4 Preparation of2-Di-n-propylamino-8-thiobenzyl-1,2,3,4-tetrahydronaphthalene

Using the procedure described in Example 1,8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (930 mg, 3.0mMol) was reacted with dibenzyl disulfide (840 mg, 3.3 mMol) to give thecrude title compound as a light yellow oil. Purification by flashchromatography (3% methanol in dichloromethane+tr. NH₄ OH) gave thedesired product as a colorless oil (630 mg, 60%). The maleate salt wasformed. Recrystallization (ethanol/diethyl ether) gave a colorless,crystalline solid (m.p.=137°-138.5° C.).

Analysis: Calculated for C₂₃ H₃₁ NS.C₄ H₄ O₄ : Theory: C, 69.05; H,7.51; N, 2.98; Found: C, 69.28; H, 7.47; N, 2.86.

MS: 353(10), 325(17), 324(63), 262(21), 253(8), 203(10), 161(10),129(25), 127(19), 91(100).

NMR (CDCl₃): 7.32-6.68(m, 8H), 4.06(s, 2H), 3.16-2.62(m, 4H),2.62-2.24(m, 4H), 2.16-1.80(m, 1H), 1.71-1.18(m, 6H), 1.08-0.72(t, J=7Hz), 6H).

Preparation Example 5 Preparation of2-Di-n-propylamino-8-methylsulfinyl-1,2,3,4-tetrahydronaphthalene

To a solution of water (60 mL) which contains methanesulfonic acid (0.16mL, 2.33 mMol) was added2-dipropylamino-8-methylthio-1,2,3,4-tetrahydronaphthalene (630 mg, 2.33mMol). To this solution was added a solution of sodium metaperiodate(550 mg, 2.57 mMol) in water (10 mL), and the reaction mixture wasstirred for two days at room temperature. The reaction mixture was madebasic (NH₄ OH) and extracted with dichloromethane. The organic extractswere combined, dried (Na₂ SO₄) and concentrated in vacuo to give thecrude title compound as a light yellow oil. Purification by flashchromatography (3% methanol in dichloromethane+tr. NH₄ OH) gave thedesired product (580 mg, 85%) as a colorless oil. The fumarate salt wasformed. Recrystallization (ethanol/diethyl ether) gave a colorless,crystalline solid which was found to be extremely hygroscopic. Drying ina vacuum dessicator (60° C., 18 hours) gave a colorless glass (260 mg,m.p.=63° C.).

Analysis: Calculated for C₁₇ H₂₇ NOS.C₄ H₄ O₄ : Theory: C, 61.59; H,7.63; N, 3.42; Found: C, 61.38; H, 7.48; N, 3.57.

MS: 294(3), 293(4), 291(1), 278(10), 277(14), 276(60), 266(12), 265(33),264(100), 250(7), 249(28), 248(8), 193(46).

NMR (CDCl₃): 7.80-7.76(m, 1H), 7.36-7.00(m, 2H), 3.28-2.20(m, 8H),2.76-2.62(d, J=3 Hz, 3H), 2.20-1.85(m, 1H), 1.80-1.20(m, 6H),1.04-0.72(t, J=7 Hz, 6H).

Preparation Example 6 Preparation of2-Di-n-propylamino-8-methylsulfonyl-1,2,3,4-tetrahydronaphthalene.

To a solution of2-dipropylamino-8-methylsulfinyl-1,2,3,4-tetrahydronaphthalene (350 mg,1.19 mMol) in trifluoroacetic acid (20 ml) was added a solution ofmetachloroperbenzoic acid (80%, 518 mg, 2.38 mMol) in trifluoroaceticacid (5 mL). The solution was stirred at room temperature for 18 hoursand poured over ice. The resulting mixture was made basic (NH₄ OH) andextracted well with dichloromethane. The organic extracts were combined,dried (Na₂ SO₄) and concentrated in vacuo to give the crude titlecompound as a brown oil. Purification by flash chromatography (3%methanol in dichloromethane+tr. NH₄ OH) gave the desired product as alight orange oil (110 mg, 30%). The maleate salt was formed.Recrystallization (ethanol/diethyl ether) gave a colorless solid (70 mg,m.p.=113°-114° C.).

Analysis: Calculated for C₁₇ H₂₇ NO₂ S.C₄ H₄ O₄ : Theory: C, 59.27; H,7.34; N, 3.29; Found: C, 59.19; H, 7.35; N, 3.18.

MS: 309(3), 283(1), 282(8), 281(18), 280(100), 209(11), 130(45).

NMR (CDCl₃): 7.88-7.76(dd, J=3 Hz, 7 Hz, 1H), 7.36-7.12(m, 2H),3.20-2.78(m, 4H), 3.08(s, 3H), 2.64-2.38(m, 4H), 2.20-1.84(m, 1H),1.80-1.14(m, 6H), 1.08-0.86(t, J=7 Hz, 6H).

Preparation Example 7 Preparation of2-Dimethylamino-8-thiomethyl-1,2,3,4-tetrahydronaphthalene

A. 2-Dimethylamino-8-bromo-1,2,3,4-tetrahydronaphthalene.

To a solution of 8-bromo-2-tetralone (4.5 gm, mMol) in acetonitrile (100mL) were added sodium acetate (9.9 gm, 120 mMol), sodiumcyanoborohydride (880 mg, 120 mMol), dimethylamine hydrochloride (9.8gm, 120 mMol) and 4A sieves (2.0 gm). The mixture was stirred at roomtemperature for 3 days. The reaction mixture was then filtered through abed of celite, and the filtrate was poured into a slurry of ice andwater.

The solution was made acidic (HCl) and extracted well with diethylether. The remaining aqueous was made basic (NH₄ OH) and extracted wellwith dichloromethane. These organic phases were combined, dried (Na₂SO₄), and concentrated in vacuo to give a dark oil. Purification byflash chromatography (5% methanol in dichloromethane+tr. NH₄ OH) gavethe title compound as a yellow oil (1.5 gm, 30%).

MS: 257(2), 256(10), 255(42), 254(18), 253(42), 252(8), 240(7), 238(8),174(13), 130(18), 129(40), 128(24), 115(20), 103(21), 84(43), 71(100),70(68).

NMR (CDCl₃): 7.55-7.18(m, 1H), 7.16-6.85(m, 2H), 3.2-2.43(m, 6H), 2.4(s,6H), 2.0-1.8(m, 1H).

B. 2-Dimethylamino-8-thiomethyl-1,2,3,4-tetrahydronaphthalene.

To a solution of 2-Dimethylamino-8-bromo-1,2,3,4-tetrahydronaphthalene(760 mg, 3 mMol) in tetrahydrofuran (20 mL) at -78° C. was addedn-butyllithium in hexane (1.6M, 3.0 mL, 4.8 mMol). The solution wasstirred at -78° C. for one hour. To the solution was then added dimethyldisulfide (0.33 mL, 4.1 mMol), and the resulting mixture was allowed towarm to room temperature. The light yellow solution was diluted withwater, made acidic (HCl), and extracted well with diethyl ether. Theremaining aqueous was made basic (NH₄ OH) and extracted well withdichloromethane. These organics were combined, dried (Na₂ SO₄), andconcentrated in vacuo to give a light yellow oil. Purification by flashchromatography (3% methanol in dichloromethane+tr. NH₄ OH) gave thedesired compound as a light yellow oil (420 mg, 63%). The hydrochloridesalt was formed. Recrystallization (acetone/diethyl ether) gave acolorless, crystalline solid (m.p.=170° C.).

Analysis: Calculated for C₁₃ H₁₉ NS.HCl: Theory: C, 60.56; H, 7.82; N,5.43; Found: C, 60.87; H, 7.94; N, 5.43.

MS: 223(4), 222(10), 221(100), 220(6), 219(1), 206(9), 177(33), 71(52).

NMR (CDCl₃): 7.2-6.8(m, 3H), 3.05-2.48(m, 5H), 2.45(s, 3H), 2.40(s, 6H),2.15-2.00(m, 1H), 1.7-1.5(m, 1H).

Preparation Example 8 Preparation ofcis-1-Methyl-2-di-n-propylamino-8-thiomethyl-1,2,3,4-tetrahydronaphthalene

A. 1-Methyl-8-bromo-2-tetralone.

To a solution of 8-bromo-2-tetralone (10 gm, 44.4 mMol) in toluene (175ml) was added pyrrolidine (6.6 ml), and the solution was stirred atreflux for three hours. The volatiles were removed in vacuo to give8-bromo-3-pyrrolidino-1,2-dihydronaphthalene as a brown oil. To this oilin p-dioxane (60 mL) was added methyl iodide (20 mL, 322 mMol), and theresulting solution was stirred at reflux for eighteen hours. Thereaction mixture was diluted with water (60 mL) and acetic acid (3.2mL), and heating was continued for an additonal three hours. After thistime the solution was cooled to room temperature and the volatilesremoved in vacuo. The residue was suspended in water and extracted wellwith diethyl ether. The organic phases were combined, washed withsaturated aqueous NaHCO₃, dried with Na₂ SO₄ and concentrated in vacuoto give an orange oil. Purification by flash chromatography (33% diethylether in hexane) gave the title compound as a light orange oil (6.88 gm,65%).

NMR (CDCl₃): 7.48-7.28(m, 1H), 7.20-6.80(m, 2H), 4.0-3.67(q, J=7.2 Hz,1H), 3.40-2.16(m, 4H), 1.48-1.28(d, J=7.2 Hz, 3H).

B. cis-1-Methyl-2-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene.

To a solution of 8-bromo-1-methyl-2-tetralone (4.05 gm, 16.9 mMol) indichloromethane (60 mL) were added magnesium sulfate (3.0 gm, 25 mMol)and n-propylamine (2.0 mL, 24.4 mMol). The mixture was stirred at roomtemperature for twenty hours. The reaction mixture was filtered througha bed of celite and the filtrate concentrated in vacuo to give1-methyl-2-n-propylimino-8-bromo-1,2,3,4-tetrahydronaphthalene as a darkresidue.

NMR (CDCl₃): 7.56-7.24(m, 1H), 7.20-6.80(m, 2H), 4.20-3.88(q, J=7.2 Hz,1H), 3.56-2.0(m, 6H), 1.88-1.52(sextet, J=5.4 Hz, 2H), 1.44-1.32(d,J=7.2 Hz, 3H), 1.16-0.84(t, J=5.4 Hz, 3H).

To a solution of the preceding dark residue in tetrahydrofuran (60 mL)were added sodium cyanoborohydride (1.8 gm, 29 mMol), and the solutionwas saturated with hydrogen chloride. The resulting mixture was stirredfor eighteen hours at room temperature. The reaction mixture was thenpoured into cold water (200 mL), made strongly basic (NaOH), and stirredfor two hours. The reaction mixture was then made acidic (HCl) andextracted well with diethyl ether. The remaining aqueous phase was madebasic (NH₄ OH) and extracted well with dichloromethane. These organicphases were combined, dried (Na₂ SO₄), and concentrated in vacuo to givea light yellow oil. Purification by flash chromatography (20% hexane indiethyl ether+tr. NH₄ OH) gave the title compound as a colorless oil(1.47 gm, 31%).

NMR (CDCl₃): 7.4-7.19(m, 1H), 7.04-6.78(m, 2H), 3.60-3.08(m, 1H),3.00-2.41(m, 4H), 1.90-1.35(m, 4H), 1.35-0.70(m, 8H).

(The trans-isomer of the title compound was also isolated as a colorlessoil (680 mg, 14%)).

C.cis-1-Methyl-2-di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene.

To a solution ofcis-1-Methyl-2-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.47gm, 5.2 mMol) in acetonitrile (30 mL) were added 1-iodopropane (0.59 mL,5.8 mMol) and proton sponge (2.2 gm, 10.4 mMol), and the mixture wasstirred at 50° C. for eighteen hours. The colorless suspension wasfiltered and the filtrate concentrated in vacuo to give a light yellowoil. Purification by flash chromatography (20% diethyl ether inhexane+tr. NH₄ OH) gave the desired compound as a colorless glass (330mg, 20%).

NMR (CDCl₃): 7.40-7.15(dd, J=3.2 Hz, 7.2 Hz, 1H), 7.0-6.68(m, 2H),3.50-3.12(m, 1H), 3.0-2.40(m, 6H), 2.0-1.68(m, 2H), 1.68-1.20(m, 5H),1.20-1.04(d, J=7.2 Hz, 3H), 1.00-0.72(t, J=5.4 Hz, 6H).

D.cis-1-Methyl-2-di-n-propylamino-8-thiomethyl-1,2,3,4-tetrahydronaphthalene.

To a solution ofcis-1-Methyl-2-n-dipropylamino-8-bromo-1,2,3,4-tetrahydronaphthalene(330 mg, 1.02 mMol) in tetrahydrofuran (10 mL) at -78° C. were addedn-butyllithium in hexane (1.6M, 1.1 mL, 1.8 mMol), and the solution wasstirred at -78° C. for one hour. To the yellow solution was addeddimethyl disulfide (0.11 mL, 1.22 mMol), and the solution was allowed towarm to room temperature. The now colorless solution was poured intowater, made acidic (HCl), and extracted well with diethyl ether. Theremaining aqueous phase was made basic (NH₄ OH) and extracted well withdichloromethane. These organic extracts were combined, dried (Na₂ SO₄),and concentrated in vacuo to give a colorless oil. Purification by flashchromatography (20% diethyl ether in hexane+tr. NH₄ OH) gave the desiredcompound as a colorless, viscous oil (240 mg, 81%). The hydrobromidesalt was formed. Recrystallization (acetone/hexane) gave a colorlesscrystalline solid (m.p.=149°-150° C.).

Analysis: Calculated for C₁₈ H₂₉ NS.HBr: Theory: C, 58.05; H, 8.12; N,3.76; Found: C, 57.84; H, 8.12; N, 3.92.

MS: 293(1), 292(3), 291(10), 290(2), 266(1), 265(6), 264(20), 262(100)192(10), 191(65), 151(25), 144(66), 115(28), 72(42).

NMR (CDCl₃): 7.16-6.66(m, 3H), 3.56-3.12(m, 1H), 3.00-2.44(m, 6H),2.40(s, 3H), 2.00-1.68(m, 2H), 1.68-1.19(m, 5H), 1.19-1.10(d, J=7.2 Hz,3H), 1.00-0.70(t, J=7.2 Hz, 6H).

Preparation Example 9 Preparation of(R)-2-Di-n-propylamino-8-thiomethyl-1,2,3,4-tetrahydronaphthalene and(S)-2-Di-n-propylamino-8-thiomethyl-1,2,3,4-tetrahydronaphthalene

A. N-[1-(4'-Nitrophenyl)ethyl]-N-(8-bromo-2-tetralin)-amine.

A solution of 50 g of Na₂ CO₃ in 300 mL of water was used to convert 66g (0.30 mol) of the hydrochloride salt of(S)-(-)-α-methyl-4'-nitrobenzylamine to its free base. The free base wasextracted into CH₂ Cl₂. This solvent was then removed under vacuum, andthe residue was dissolved in 700 mL of acetonitrile. To this solutionwere added successively 4.5 mL (0.08 mol) of HOAc, 4.9 g (0.08 mol) ofNaCNBH₃, 65 g (0.29 mol) of 8-bromo-2-tetralone, and 20 g of 3Amolecular sieves. The mixture was stirred under nitrogen for 16 h.Another 31.4 g (0.50 mol) of NaCNBH₃ was added, followed by 13.5 mL(0.24 mol) of HOAc. After 4 more hours an addition of 2 mL of HOAc wasmade, followed at two hour intervals by two more such additions. Afterstirring for another 16 h the mixture was filtered, and most of theacetonitrile was removed under vacuum. The residual mixture was pouredinto cold Na₂ CO₃ solution and extracted with CH₂ Cl₂. The extract waswashed with NaCl solution and dried over Na₂ SO₄. The CH₂ Cl₂ wasevaporated leaving the crude product as a viscous brown oil. The crudeproduct was taken up in 300 mL of ether and then extracted into asolution of 50 g of tartaric acid in 1.5 L of 30% methanol in water. Theaqueous layer was washed twice with fresh ether, then basified with sat.Na₂ CO₃ solution and extracted into CH₂ Cl₂. This extract was washedwith NaCl solution and dried over Na₂ SO₄. Removal of the solvent undervacuum gave 84.9 g (78% yield) of the product as an amber oil whichappeared to be clean by NMR.

B. N-[1-(4'-Nitrophenyl)ethyl]-N-(8-bromo-2-tetralin)propionamides.

The compound from Part A (84.9 g, 0.23 mol) was dissolved in 1 L of CH₂Cl₂. This solution was treated with 71 mL (0.51 mol) of triethylamineand then slowly with 42 mL (0.48 mol) of propionyl chloride. The mixturewas stirred for 16 h. It was then treated with cold Na₂ CO₃ solution.After stirring vigorously for three hours, the CH₂ Cl₂ layer wasseparated. This solution was washed with aqueous tartaric acid solutionand then with Na₂ CO₃ solution. After drying over Na₂ SO₄, the CH₂ Cl₂was evaporated leaving 101 g of the crude diastereomeric mixture ofamides. The diastereomers were separated by chromatographing in 20-30 gruns on an HPLC system that employed columns containing about 400 g ofsilica gel ("Prep 500"). The solvent system was a gradient proceedingfrom pure toluene to 20% EtOAc in toluene. The total weight of the firstdiastereomer (S,R) from the column was 49.6 g. The second diastereomer(S,S) weighed 40.6 g. Both diastereomers were viscous oils. Bothcontained about 2% toluene. A satisfactory analysis was obtained for theS,S diastereomer after rigorous drying of a small sample. Slightly highcarbon and low bromine percentages in the sample of the S,R diastereomersuggested that a trace of solvent had persisted even after drying.Yields of the two diastereomers were approximately 48% and 40%,respectively.

(S,R)-Diastereomer:

OR: [α]_(D) ²⁵ +9.4° (C=10, MeOH)

Analysis: Calculated for C₂₁ H₂₃ BrN₂ O₃ : Theory: C, 58.48; H, 5.38; N,6.49; Br, 18.53; Found: C, 60.07; H, 5.61; N, 6.28; Br, 17.76.

MS: 433(1), 431(1), 361(3), 359(3), 210(100), 208(100), 129(67), 57(54).

UV (EtOH): λ_(max) 271 nm (ε9600)

IR (CHCl₃): λ_(max) 1642 cm⁻¹

(S,S)-Diastereomer:

OR: [α]_(D) ²⁵ -114° (C=10 MeOH)

Analysis: Calculated for C₂₁ H₂₃ BrN₂ O₃ : Theory: C, 58.48; H, 5.38; N,6.49; Br, 18.53; Found: C, 58.66; H, 5.43; N, 6.37; Br, 18.33.

MS: 433(1), 431(1), 361(5), 359(5), 210(100), 208(100), 129(99), 57(92).

UV (EtOH): λ_(max) 273 nm (ε9000)

IR (CHCl₃): λ_(max) 1642 cm⁻¹

C.(S,R)-N-[1-(4'-Nitrophenyl)ethyl]-N-(8-bromo-2-tetralin)-1-propylamine.

A solution of 49 g (0.114 mol) of the S,R-diastereomer from Part B in200 mL of THF was added gradually to 230 mL of ice cooled 1M borane inTHF. The solution was then refluxed under nitrogen for 2 h. After thesolution was allowed to cool, it was carefully treated with 100 mL ofMeOH. This solution was stirred for 1 h. The solvents were evaporatedunder vacuum, and the residue was taken up in a mixture of 250 mL ofDMSO and 30 mL of water. This solution was heated on a steam bath for 1h. It was then cooled and extracted with CH₂ Cl₂. The extracts werewashed with NaCl solution and dried over Na₂ SO₄. The CH₂ Cl₂ wasevaporated, and the crude free base was converted to its HCl salt bydissolving in 1 L of ether and adding 50 mL of 2.6M HCl in ether. Thesalt was collected and washed with fresh ether. The dried salt, whichweighed 50.4 g (97% yield), analyzed satisfactorily.

OR: [α]_(D) ²⁵ +28° (C=10, MeOH)

Analysis: Calculated for C₂₁ H₂₅ BrN₂ O₂.HCl: Theory: C, 55.58; H, 5.78;N, 6.17; Cl, 7.81; Br, 17.61; Found: C, 55.32; H, 5.94; N, 5.97; Cl,7.61; Br, 17.33.

MS: 418(14), 416(15), 389(73), 387(71), 240(61), 238(68), 130(100),104(59).

UV (EtOH): λ_(max) 267 nm (ε10,000)

D. (S,S)-N-[1-(4'-Nitrophenyl)ethyl]-N-(8-bromo-2-tetralin)propylamine.

The reduction procedure described in Part C was used to reduce 40 g(0.093 mol) of the S,S diastereomer of the analogous amide. Elementalanalysis indicated that the crude HCl salt, obtained in 98% yield, wasslightly impure.

OR: [α]_(D) ²⁵ -94° (C=10 MeOH)

Analysis: Calculated for C₂₁ H₂₅ BrN₂ O₂.HCl: Theory: C, 55.58; H, 5.78;N, 6.17; Found: C, 55.13; H, 5.94; N, 5.69.

MS: 418(21), 416(20), 389(79), 387(78), 240(54), 238(57), 130(100),104(74).

UV (EtOH): λ_(max) 269 nm (ε10,000)

E. (R)-8-Bromo-2-(N-propylamino)tetralin.

A solution of 12.5 g (27.6 mmol) of the HCl salt from Part C (S,Rdiastereomer) in 200 mL of MeOH was hydrogenated for 8 h at 40 psi over0.5 g of sulfided 5% platinum on carbon. After filtering off thecatalyst, most of the MeOH was evaporated under vacuum without heat.Thorough ether washing of the methanolic slurry that remained afforded6.55 g (78% yield) of the HCl salt of the title compound. A satisfactoryanalysis was obtained without without further purification.

OR: [α]_(D) ²⁵ +54° (C=8 MeOH)

Analysis: Calculated for C₁₃ H₁₈ BrN.HCl: Theory: C, 51.25; H, 6.29; N,4.60; Br, 26.23; Cl, 11.64; Found: C, 51.48; H, 6.41; N, 4.47; Br,26.25; Cl, 11.63.

MS: 269(24), 267(23), 240(63), 238(66), 211(30), 209(34), 130(85),56(100).

NMR (DMSOd₆): δ0.97 (t, 3H), 1.71 (sextet, 2H), 1.79 (sextet, 1H), 2.27(broad d, 1H), 2.75 (qt, 1H), 2.88 (broad t, 2H), 2.96 (mult, 2H), 3.25(qt, 1H), 3.48 (broad mult, 1H), 7.12 (t, 1H), 7.18 (d, 1H), 7.49 (d,1H), 9.19 (broad s, 2H).

F. (S)-8-Bromo-2-(N-propylamino)tetralin.

Hydrogenation of the HCl salt of the S,S diastereomeric amine from PartD in a manner analogous to that described above gave a 94% yield of theHCl salt of the title compound. In this case the crude product showedminor impurities. A small sample was recrystallized from i-PrOH foranalysis OR:

[α]_(D) ²⁵ -54° (C=10, MeOH)

Analysis: Calculated for C₁₃ H₁₈ BrN.HCl:

Theory: C, 51.25; H, 6.29; N, 4.60; Br, 26.23; Cl, 11.64; Found: C,51.31; H, 6.30; N, 4.41; Br, 26.44; Cl, 11.81.

MS: 269(24), 267(23), 240(63), 238(66), 211(30), 209(34), 130(85),56(100).

NMR (DMSOd₆): δ0.97 (t, 3H), 1.71 (sextet, 2H), 1.79 (sextet, 1H), 2.27(broad d, 1H), 2.75 (qt, 1H), 2.88 (broad t, 2H), 2.96 (mult, 2H), 3.25(qt, 1H), 3.48 (broad mult, 1H), 7.12 (t, 1H), 7.18 (d, 1H), 7.49 (d,1H), 9.19 (broad s, 2H).

G. (S)-8-Bromo-N,N-dipropyl-2-aminotetralin.

To a solution of (S)-8-Bromo-N-propyl-2-aminotetralin (5.0 gm, 18.6mMol) as produced in Part F in acetonitrile (75 mL) were added n-propyliodide (3.0 mL, 31 mMol), followed by powdered potassium carbonate (4.0gm, 29 mMol), and the reaction mixture was stirred for the weekend at50° C. The reaction mixture was then cooled to room temperature andfiltered. The filtrate was concentrated in vacuo to give a yellow oil.Purification by flash chromatography (2:1 hexane:diethyl ether+tr. NH₄OH) gave the title compound as a colorless oil (3.6 gm, 62%).

NMR (CDCl₃): δ7.39(d, J=8.01 Hz, 1H), 6.98(m, 2H), 2.90(m, 4H), 2.53(m,5H), 2.02(m, 1H), 1.50(m, 5H), 0.91(t, J=7.30 Hz, 6H).

H. (R)-8-Bromo-N,N-dipropyl-2-aminotetralin.

(R)-8-Bromo-N-propyl-2-aminotetralin (10.5 gm, 39.2 mMol) as produced inPart E was treated as described in Part G to give the title compound asa colorless oil (9.6 gm, 80%). The NMR spectrum recorded for thiscompound was identical to the spectrum recorded for the compound of PartG.

I. (S)-8-Thiomethyl-N,N-dipropyl-2-aminotetralin hydrochloride.

To a solution of (S)-8-Bromo-N,N-dipropyl-2-aminotetralin (16.4 gm, 52.9mMol) from Part G in tetrahydrofuran (400 mL) at -78° C. were added asolution of n-butyllithium in hexane (1.6M, 39.7 mL, 63.5 mMol), and thesolution was allowed to stir at this temperature for 1.5 hours. To thesolution were then added dimethyl disulfide (9 mL, 100 mMol), and thereaction mixture was allowed to warm gradually to room temperature. Thereaction mixture was then diluted with water and made acidic with 10%hydrochloric acid. The aqueous mixture was then extracted once withdiethyl ether and the ether phase discarded. The remaining aqueous wasmade strongly basic with ammonium hydroxide and then was extracted wellwith dichloromethane. The organic extracts were combined, washed withsaturated aqueous sodium chloride, dried over sodium sulfate, andconcentrated in vacuo to give a yellow oil. Purification by flashchromatography (2:1 hexane:diethyl ether+tr. NH₄ OH) gave a light yellowoil. This oil in diethyl ether was converted to the hydrochloride salt.Crystallization (ethanol/diethyl ether) gave the title compound as acolorless, crystalline solid (11.7 gm, 70%, m.p.=178.5°-180° C.).

OR: [α]_(D) ²⁰ (H₂ O)=-65.14°

Analysis: Calculated for C₁₇ H₂₇ NS.HCl: Theory: C, 65.04; H, 8.99; N,4.46; Found: C, 65.32; H, 9.13; N, 4.48.

MS: 278(6), 277(19), 250(7), 249(20), 248(100), 179(18), 178(23),177(67), 130(47), 129(39), 128(32).

NMR (CDCl₃) δ7.13(t, J=9 Hz, 1H), 7.00(d, J=9 Hz, 1H), 6.90(d, J=9 Hz,1H), 2.95(m, 4H), 2.50(m, 5H), 2.48(s, 3H), 2.03(m, 1H), 1.54(m, 5H),0.92 (t, J=6 Hz, 6H).

J. (R)-8-Thiomethyl-N,N-dipropyl-2-aminotetralin hydrochloride.

(R)-8-Bromo-N,N-dipropyl-2-aminotetralin (17 gm, 54.8 mMol) from Part Hwas treated as described in Part I to give the title compound as acolorless, crystalline solid (10.5 gm 61%, m.p.=177.5°-178.5° C.).

OR: [α]_(D) ²⁰ (H₂ O)=+64.85°

Analysis: Calculated for C₁₇ H₂₇ NS.HCl: Theory: C, 65.04; H, 8.99; N,4.46; Found: C, 65.32; H, 9.02; N, 4.50.

Preparation Example 10 Preparation of3-(Di-n-propylamino)-5-methylthio-chromane hydrochloride.

A. Allyl 3-bromophenyl ether.

The title compound was synthesized in 91% yield from 3-bromophenol bythe procedure described in Journal of Organic Chemistry, 26, 3631,(1961).

B. 2-Allyl-3-bromophenol.

The title compound was synthesized from allyl 3-bromophenyl ether by anortho Claisen rearrangement in dimethylaniline as described in HelveticaChemica Acta, 56(1), 14, (1973).

C. 2-Allyl-3-(carboxymethoxy)bromobenzene.

To a solution of the product from Part B (15.2 gm, 71.4 mMol) inacetonitrile (350 mL) were added ethyl chloroformate (9.6 gm, 78.5 mMol)and potassium carbonate (19.7 gm, 143 mMol). The reaction mixture wasstirred at 60° C. for 66 hours. After this time the reaction mixture wasfiltered and concentrated in vacuo to give the crude product as a lightyellow oil. Purification by flash chromatography (1:1 hexane:diethylether) gave the desired compound as a colorless oil (16.6 gm, 78%).

NMR(CDCl₃): δ7.22(d, J=8.05 Hz, 1H), 7.03(t, J=8.12 Hz, 1H), 6.70(d,J=8.26 Hz, 1H), 6.00(m, 1H), 5.02(m, 2H), 4.64(s, 2H), 4.27(q, J=7.22Hz, 2H), 3.67 (d, J=6.25 Hz, 2H), 1.30(t, J=7.08 Hz, 3H ).

D. 2-Formylmethyl-3-(carboxymethoxy)bromobenzene.

A solution of the product from Part C (16.6 gm, 55.5 mMol) in absoluteethanol (500 mL) was cooled to -78° C., and then ozone was bubbled intothe reaction mixture. After 20 minutes the solution had become lightblue and all of the starting material had been consumed (TLC 1:1hexane:diethyl ether). The reaction mixture was allowed to warmgradually to room temperature. At this point a colorless solid hadprecipitated, and the suspension was again cooled to -78° C. Dimethylsulfide (7.3 mL, 100 mMol) was added dropwise, and then the reactionmixture was allowed to warm gradually to room temperature. Volatileswere removed in vacuo to give the title compound as a light yellow oil(18.3 gm, 100+ %).

IR(thin film): 1022.5, 1073.1, 1189.7, 1203.7, 1725.4, 1754.7 cm⁻¹.

MS(FD): 302(100), 300(90).

NMR (CDCl₃): δ9.70(s, 1H), 7.25(d, J=8.06 Hz, 1H), 7.11(t, J=8.16 Hz,1H), 6.74(d, J=8.13 Hz, 1H), 4.62(s, 2H), 4.22(q, J=7.14 Hz, 2H),4.00(s, 2H), 1.26(t, J=6.81 Hz, 3H).

E. 2-Carboxymethyl-3-(ethoxycarbonylmethoxy)bromobenzene.

To approximately 55 mMol of crude product from Part D in acetone (300mL) were added Jones' Reagent until a bright orange color persists insolution. A dark green solid formed as the temperature graduallyincreased to reflux. Isopropanol was added to destroy any excesschromium trioxide, and then the reaction mixture was diluted with waterand then extracted well with diethyl ether. The ether phases werecombined and then washed well with water. The remaining ether phase wasextracted three times with saturated aqueous sodium bicarbonate (100mL). These extracts were then made strongly acidic with hydrochloricacid (10%) and extracted well with chloroform:isopropanol (3:1). Thecombined organic extracts were then washed with saturated aqueous sodiumchloride, dried over sodium sulfate and concentrated in vacuo to givethe title compound as a yellow viscous oil (12.3 gm, 71%).

IR(thin film): 1191.1, 1205.8, 1278.8, 1449.3, 1465.3, 1574.6, 1171.1,1739.3, 1754.8 cm⁻¹.

MS(FD): 318(100), 316(90).

NMR (CDCl₃): δ7.26(d, J=8.14 Hz, 1H), 7.12(t, J=8.17 Hz, 1H), 6.75(d,J=8.12 Hz, 1H), 4.66(s, 2H), 4.25(q, J=6.84 Hz, 2H), 4.04(s, 2H),1.29(t, J=7.22 Hz, 3H).

F. 2-Carboxymethyl-3-(carboxymethoxy)bromobenzene, diethyl ester.

A solution of the product from Part E (12.3 gm, 38.8 mMol) in absoluteethanol (400 mL) was saturated with hydrogen chloride, and the solutionwas allowed to stir for 18 hours at room temperature. Volatiles wereremoved in vacuo to give a light brown oil. Purification by flashchromatography (1:1 hexane:diethyl ether) gave the desired compound as acolorless oil (12.4 gm, 93%).

NMR(CDCl₃): δ7.24(d, J=8.09 Hz, 1H), 7.10(t, J=8.53 Hz, 1H), 6.73(d,J=8.13 Hz, 1H), 4.63(s, 2H), 4.21(m, 4H), 3.97(s, 2H), 1.27(m, 6H).

G. Mixture of 4-Ethoxycarbonyl-5-bromo-3-chromanone and2-ethoxycarbonyl-5-bromo-3-chromanone.

A solution of the diester from Part F (6 gm, 17.4 mMol) intetrahydrofuran (50 ml) was added dropwise to a solution of potassiumt-butoxide (3.90 gm, 34.8 mMol) in tetrahydrofuran (200 mL). Thereaction mixture was then immediately poured over ice and the solutionmade acidic with 10% hydrochloric acid. The mixture was then extractedwell with diethyl ether. The organic phases were combined, washed withsaturated aqueous sodium chloride, dried over sodium sulfate, andconcentrated in vacuo to give a yellow solid. Purification by flashchromatography (1:1 hexane:diethyl ether) gave two compounds.2-Ethoxycarbonyl-5-bromo-3-chromanone was recovered as colorlesscrystals (1.3 gm).

NMR(CDCl₃): δ7.25(d, J=8.10 Hz, 1H), 7.05(m, 2H), 4.42(q, J=6.84 Hz,2H), 3.70(s, 2H), 1.58(br s, 1H), 1.42(t, J=7.10 Hz, 3H).

The 4-ethoxycarbonyl-5-bromo-3-chromanone was recovered as a lightyellow viscous oil (1.7 gm).

NMR(CDCl₃): δ7.26(d, J=8.14 Hz, 1H), 7.18(t, J=8.18 Hz, 1H), 7.04(d,J=8.12 Hz, 1H), 4.90(s, 1H), 4.75(d, J=16 Hz, 1H), 4.22(m, 3H), 1.27(t,J=7.05 Hz, 3H).

Total yield for cyclized product was 3.0 gm (58%).

H. 5-Bromo-3-chromanone.

A suspension of 2-ethoxycarbonyl-5-bromo-3-chromanone (300 mg, 1 mMol)in methanol (5 mL) and 10% hydrochloric acid (3 mL) was heated at refluxfor 2 hours. All of the solid had not dissolved; therefore,trifluoroacetic acid (1 mL) was added, and heating was continued for 18hours. The reaction mixture was diluted with water and extracted wellwith diethyl ether. The ether phases were combined, dried over sodiumsulfate, and concentrated in vacuo to give a yellow glass. Purificationby flash chromatography (1:1 hexane:ether) gave the title compound as alight yellow glass (120 mg, 53%).

NMR(CDCl₃): δ7.32(d, J=8.08 Hz, 1H), 7.12(t, 8.19 Hz, 1H), 7.02(d,J=8.05 Hz, 1H), 4.41(s, 2H), 3.69(s, 1H).

I. 5-Bromo-3-di-n-propyl-3-aminochromane.

To a solution of the product from Part H (620 mg, 2.73 mMol) in toluene(20 mL) were added dipropylamine (0.7 mL, 6 mMol) and p-toluenesulfonicacid (100 mg, 0.52 mMol), and the mixture was heated at reflux withconstant water removal (Dean-Stark trap). After 3 hours the reactionmixture was cooled to room temperature and the volatiles removed invacuo to give a dark reddish-orange residue. This material was dissolvedin tetrahydrofuran (40 mL), sodium cyanoborohydride (400 mg, 6.4 mMol)was added and the solution was saturated with hydrogen chloride. Thereaction mixture was stirred for 18 hours at room temperature. Thereaction mixture was then poured into 15% sodium hydroxide (100 mL) andwas stirred vigorously for 2 hours. The reaction mixture was thenextracted well with diethyl ether. The organic phases were combined,dried over sodium sulfate, and concentrated in vacuo. The residue wassuspended in 10% hydrochloric acid and the aqueous extracted once withdiethyl ether. This ether extract was discarded and the remainingaqueous made basic with concentrated ammonium hydroxide and thenextracted well with dichloromethane. The combined organics were washedwith saturated aqueous sodium chloride, dried over sodium sulfate, andconcentrated in vacuo to give a light yellow oil. Purification by flashchromatography (4:1 hexane:diethyl ether+tr. NH₄ OH) gave the titlecompound as a colorless oil (420 mg, 50%).

NMR(CDCl₃): δ7.16(d, J=7.77 Hz, 1H), 6.98(t, J=7.85 Hz, 1H), 6.80(d,J=8.16 Hz, 1H), 4.28(m, 1H), 3.78(t, J=8.30 Hz, 1H), 3.17(m, 1H),2.93(m, 1H), 2.67(m, 1H), 2.53(t, J=7.42 Hz, 4H), 1.49(sextet, J=7.32Hz, 0.91(t, J=7.28 Hz, 6H).

J- 3-Di-n-propyl-amino-5-thiomethyl-chromane hydrochloride.

To a solution of the product from Part I (420 mg, 1.35 mMol) intetrahydrofuran (25 mL) at -78° C. was added a solution ofn-butyllithium in hexane (1.6M, 2 mL, 3.2 mMol), and the resultingsolution was stirred at -78° C. for 1 hour. To the mixture was thenadded dimethyl disulfide (0.25 mL, 2.5 mMol), and the reaction mixtureallowed to warm gradually to room temperature. The reaction mixture wasdiluted with water and made acidic with hydrochloric acid. The aqueouswas then extracted well with diethyl ether, and the ether extracts werediscarded. The remaining aqueous was made basic with concentratedammonium hydroxide and extracted well with dichloromethane. The organicswere dried over sodium sulfate and concentrated in vacuo to give acolorless oil. Purification by flash chromatography (1:1 hexane:diethylether+tr. NH₄ OH) gave a colorless, viscous oil (290 mg, 77%). Thehydrochloride salt was formed. Recrystallization (ethanol/diethyl ether)gave the title compound as colorless crystals (m.p.=181°-183° C.).

Analysis: Calculated for C₁₆ H₂₅ NOS.HCl: Theory: C, 60.83; H, 8.30; N,4.43; Found: C, 61.09; H, 8.32; N, 4.44.

MS: 280(6), 279(28), 252(8), 251(23), 250(100), 179(74), 98(50).

NMR(CDCl₃): δ7.10(t, J=8.01 Hz, 1H), 6.75(d, J=7.89 Hz, 1H), 6.63(d,J=7.97 Hz, 1H), 4.30(m, 1H), 3.78(t, J=8.30 Hz, 1H), 3.20(m, 1H),2.89(m, 1H), 2.56(m, 5H), 2.45(s, 3H), 1.48(sextet, J=7.32 Hz, 4H),0.91(t, J=7.31 Hz, 6H).

4-amino-1,3,4,5-tetrahydrobenz[c,d]indoles

A second class of direct acting 5HT1A agonists comprises the4-amino-1,3,4,5-tetrahydrobenz[c,d]indoles. Representative examples ofcompounds within this class include those disclosed in EPA 153083,published Aug. 28, 1985, which describes4-amino-6-substituted-1,3,4,5-tetrahydrobenz[c,d] indoles having theFormula ##STR8## wherein AM is NR⁴ R⁵ wherein R⁴ and R⁵ are individuallyhydrogen, methyl, ethyl, n-propyl or allyl, and X¹ is OC₁₋₃ alkyl,O-acyl, OH, a halogen, CN, CONH₂ NH₂ or NO₂ ; and pharmaceuticallyacceptable salts thereof.

Compounds according to this Formula have an asymmetric center at C-4. Assuch, each of the compounds exists as its individual d- and1-stereoisomers as well as the racemic mixture of such isomers.Accordingly, the compounds of the present invention include not only thedl-racemates but also their respective optically active d- and1-isomers.

EPA Publication No. 153,083 which is incorporated by reference herein inits entirety also describes methods for preparing these compounds.

U.S. Pat. No. 4,745,126, which is incorporated by reference herein inits entirety describes additional examples of and methods for preparingcompounds within the scope of the above Formula II, includingstereoisomers and pharmaceutically acceptable salts.

Further examples of 1,3,4,5-tetrahydrobenz[c,d]indoles includingpharmaceutically acceptable salts and stereoisomers are those disclosedin EPA 0148440 published Jul. 17, 1985 which is incorporated byreference herein in its entirety. The compounds disclosed in EPA 0148440have the above Formula II where X is C₁ -C₄ alkoxy, OH, SH or C₁ -C₄alkylthio, and R⁴ and R⁵ are hydrogen, C₁ -C₆ alkenyl, or, together withthe N atom, form a 5-or 6-membered heterocyclic ring which canoptionally be substituted by 1 or 2 C₁ -C₆ alkyl groups. Methods forpreparing the compounds, including 6-mercapto and 6-alkylthioderivatives, are described.

Still further examples of 1,3,4,5tetrahydrobenz[c,d]indoles within thissecond class are those having the Formula ##STR9## wherein: R⁶ ishydrogen, C₁ -C₄ alkyl, allyl or ##STR10## R⁷ is hydrogen, C₁ -C₄ alkylor allyl; R⁸ is hydrogen, C₁ -C₃ alkoxy or C₁ -C₃

alkylthio;

R⁹ is hydrogen, methyl, ethyl or vinyl;

X² is O or S; or

a pharmaceutically acceptable salt thereof.

In the above Formula IIA, C₁ -C₄ alkyl represents a straight or branchedalkyl chain having from one to four carbon atoms. Typical C₁ -C₄ alkylgroups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyland the like.

C₁ -C₃ Alkoxy represents methoxy, ethoxy, n-propoxy and isopropoxy.

C₁ -C₃ Alkylthio represents methylthio, ethylthio, n-propylthio andisopropylthio.

Preferably X² is oxygen, R⁶ and R⁷ are both C₁ -C₄ alkyl, and especiallyn-propyl, and R⁸ is C₁ -C₃ alkoxy, and especially methoxy or ethoxy.

As pointed out above, the Formula IIA compounds includes thepharmaceutically-acceptable salts of those compounds. Since thesecompounds are amines, they are basic in nature and accordingly reactwith any number of inorganic and organic acids to form pharmaceuticallyacceptable salts such as hydrochloric acid, nitric acid, phosphoricacid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acidand others, as well as salts derived from non-toxic organic acids suchas aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxyalkanoic and hydroxyalkandioic acid, aromatic acids,aliphatic and aromatic sulfonic acids. Such pharmaceutically-acceptablesalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, acrylate, formate, tartrate isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, phthalate,terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, malate, naphthalene-1-sulfonate, naphthalene-2-sulfonate andmesylate.

The compounds of Formula IIA have an asymmetric center at the carbonatom at the 4-position of the tetrahydrobenz[c,d]indole ring. As suchthe compounds can exist as either the racemic mixture, or as theindividual stereoisomers. All such types of compounds are contemplatedby the leave as is.

The following list illustrates representative compounds of Formula IIA.

(±)-4-(dimethylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbothioicacid, S-methyl ester

(±)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbothioicacid, O-ethyl ester

(+)-4-(methylethylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbodithioicacid, methyl ester

(+)-4-(n-butylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, ethyl ester

(-)-4-(n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbothioicacid, S-methyl ester

(±)-4-amino-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbodithioic acid,n-propyl ester

(+)-4-(allylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbodithioicacid, ethyl ester

(±)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbothioicacid, S-methyl ester

(-)-4-(methylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylic acid,n-propyl ester

(+)-4-amino-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylic acid, methylester

(±)-4-(diethylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, n-propyl ester maleate

(±)-4-(dimethylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, methyl ester

(-)-4-(methylisopropylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbothioicacid, O-methyl ester

(+)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxaldehyde

(±)-4-(ethylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbothioic acid,S-methyl ester

(±)-4-(methylethylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, ethyl ester

(+)-4-(sec.-butylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carbodithioicacid, methyl ester

Among the 5-HT1A agonist compounds included in this class as describedabove, including these compounds described in references that have beenincorporated by reference, certain of these compounds are preferred. Thepreferred compounds are those of Formula II

where

R⁴ and R⁵ are individually selected from hydrogen, methyl, ethyl,n-propyl and allyl;

X¹ is OH, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, O-acyl, halogen, CN, CONH₂,NH₂, NO₂, COO(C₁ -C₃ alkyl), CHO, or C(O)S (C₁ -C₃) alkyl; or apharmaceutically acceptable acid addition salt thereof.

The compounds of Formula IIA are preferably prepared by the followingprocess. A 4-amino-6-bromotetrahydrobenz[c,d]indole is converted to a1-potassium-6-lithium substituted derivative which is treated with anappropriate electrophile. The compound thus prepared may requiredeblocking to provide a compound of Formula IIA. This reaction may berepresented by the following scheme: ##STR11## wherein R⁶, R⁷, R⁸ and X²are as defined above.

According to this process, a 4-amino-6-bromotetrahydrobenz[c,d]indole 1is combined with an equimolar to slight excess amount of potassiumhydride in diethyl ether. The reagents are generally combined at a coldtemperature, typically in the range of about -20° C. to about 10° C.,preferably at about 0° C. The resulting mixture is next cooled to atemperature in the range of about -100° C. to about -60° C., preferablyat about -78° C., and combined with a lithiating reagent, preferably inat least a two molar excess amount. Suitable lithiating reagents areselected from the group consisting of sec-butyllithium andt-butyllithium, which is preferred. The reaction is substantiallycomplete after about 10 minutes to about 6 hours when conducted at atemperature in the range of about -100° C. to about -20° C., preferablyat about -60° C. to about -40° C.

The 4-amino-6-lithiumtetrahydrobenz[c,d]indole 2 thus prepared is nextconverted to the 1,6-disubstituted-4-aminotetrahydrobenz[c,d]indole 3upon reaction with an appropriate electrophile such as R⁸ C(═X)Y whereinX is defined above and Y is a good leaving group such as cyano.Typically, a solution of the compound 2 at a temperature in the range ofabout -100° C. to about -60° C., preferably at about -80° C., is addedto a solution of this reagent in a mutual solvent. Typically at least afour molar excess amount of the electrophile is employed in thereaction. The reaction is substantially complete after about 10 minutesto about 2 hours when conducted at a temperature in the range of about-40° C. to about 10° C. The desired compound is purified by quenchingthe reaction mixture with ice water. The mixture is washed with a waterimmiscible organic solvent. The organic phase is extracted with acid,and the aqueous phases are combined, made basic and the desired compoundextracted with a water immiscible organic solvent. The organic solventis then concentrated, typically under vacuum, and the desired compound 3is further purified, if necessary, by standard procedures.

If any nitrogen atoms are acylated in the foregoing reactions thecompounds of Formula IIA are prepared according to standard deblockingconditions. Deblocking generally occurs in base, such as ammoniumhydroxide or an inorganic base, for example potassium carbonate, in aprotic solvent such as alcohol or water. The desired compound isisolated by standard conditions and purified by crystallization fromcommon solvents or column chromatography over solid supports such assilica gel or alumina.

Thiocarboxylic acid esters defined by Formula IIA wherein X² is sulfurform another important group of compounds that are a further embodimentof this class of compounds. The thiocarboxylic acid esters of theinvention may be prepared by thiating the corresponding carboxylic acidester or thioester. Any of several thiating agents can be employed inthis reaction including phosphorous pentasulfide. Another preferredthiating agent is Lawesson's Reagent, which is2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide.This thiating agent and its general uses are described in detail inTetrahedron Letters, 21, 4061 (1980). The thiation reaction ispreferably carried out by combining approximately equimolar quantitiesof the carboxylic acid ester and thiating agent in a mutual organicsolvent such as toluene or dioxane. The reaction is generally completewithin about 1 hour to about 10 hours when carried out at a temperatureof about 50° C. to about 150° C. The thiocarboxylic acid esters thusformed can be isolated and purified by normal methods such ascrystallization and the like.

The thiocarboxylic acid esters of Formula IIA may also be prepared byreacting the 4-amino-6-lithiumtetrahydrobenz[c,d]indole 2, prepared asdescribed above, with a thiocarbonyl reagent such as carbon disulfide orthiocarbonyl-1,1'-diimidazole, which can then be converted to a compoundof Formula IIA by reaction with the desired electrophile as describedabove.

The compounds of Formula IIA wherein the 6-position has a carboxylicacid group may be used as intermediates to certain other compounds ofFormula IIA. For example, the 6-carboxylic or 6-thiocarboxylic acids maybe reacted with a reagent R⁸ H (wherein R⁸ is other than hydrogen) and acoupling reagent, for example any of the type of coupling reagentscommonly employed in the synthesis of peptides, and the desired ester orthioester isolated. Examples of such coupling reagents includecarbodiimides, such as N,N'-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide or N,N'-diethylcarbodiimide; the imidazolessuch as carbonyl diimidazole as well as reagents such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

The compounds of Formula IIA wherein R⁸ is hydrogen are carboxaldehydesand may be prepared by reducing a4-amino-6-cyanotetrahydrobenz[c,d]indole with a hydride reducing agentsuch as diisobutylaluminum hydride, and isolating the desired compoundof Formula IIA according to standard procedures.

The pharmaceutically acceptable salts of the invention are typicallyformed by reacting an amine of Formula IIA with an equimolar or excessamount of acid. The reactants are generally combined in a mutual solventsuch as diethyl ether or benzene, and the salt normally precipitates outof solution within about one hour to about 10 days, and can be isolatedby filtration.

The 4-amino-6-bromo tetrahydrobenz[c,d]indole and 6-cyano and6-carboxylic acid starting materials used to prepare the compounds ofthe invention are known compounds readily prepared by prior artprocesses. The compounds are taught in detail by Flaugh in U.S. Pat. No.4,576,959, incorporated by reference herein in its entirety.

The following Examples further illustrate the compounds of Formula IIAand methods for their synthesis.

Preparation Example 11(±)-4-(Di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, methyl ester

A.(±)-1-Methoxycarbonyl-4-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, methyl ester

A solution of 0.335 g (1 mmol) of4-(di-n-propylamino)-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole in 5 mlof diethyl ether was added to a suspension of 0.19 g (1.2 mmol) ofpotassium hydride in a 25% by weight mineral oil dispersion in 25 ml ofdiethyl ether at about 0° C. The reaction mixture was stirred at 0° C.for 1 hour and cooled to approximately -78° C. with an external dryice/acetone bath. A solution of 1.7M t-butyllithium (1.5 ml, 2.55 mmol)cooled to about -78° C. was added to the reaction mixture via a cannula.The resulting mixture was allowed to warm to approximately -40° C. andwas stirred at that temperature for 2 hours. The turbid mixture wascooled to -78° C. and a solution of 0.34 g (4 mmol) of methylcyanoformate in 1 ml of diethyl ether was rapidly added. The mixture wasallowed to warm to about 0° C. and was quenched with ice water. Themixture was extracted with diethyl ether. The ether extract wasextracted with 1M phosphoric acid. The aqueous solution was treated withan excess amount of a saturated aqueous sodium bicarbonate solution andextracted with methylene chloride. The organic extract was dried overanhydrous sodium sulfate and concentrated under vacuum. The resultingresidue was chromatographed over 5 g of silica gel while eluting firstwith ethyl acetate:toluene (1:9, v:v) followed by ethyl acetate:toluene(1:1, v:v). Fractions containing the major component were combined andthe solvent was evaporated therefrom to provide 261 mg of(±)-1-methoxycarbonyl-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, methyl ester.

B. A solution of 261 mg (0.64 mmol) of(±)-1-methoxycarbonyl-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, methyl ester in 10 ml of methanol was added to a solution of 2.0 gof potassium carbonate in 10 ml of water and 20 ml of methanol. Theresulting mixture was stirred at room temperature for approximately 1hour and a thin layer chromatograph indicated that only a trace ofstarting material remained. The reaction mixture was diluted with anaqueous saturated sodium chloride solution and extracted several timeswith methylene chloride. The organic extracts were combined and washedwith an aqueous sodium chloride solution and dried over anhydrous sodiumsulfate. The organic phase was concentrated under vacuum to dryness toprovide a crystalline residue which was recrystallized fromtoluene/hexane to provide 154 mg of(±)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]-indole-6-carboxylicacid, methyl ester. mp=132°-132.5° C.

Analysis calculated for C₁₉ H₂₆ N₂ O₂ Theory: C, 72.58; H, 8.34; N,8.91; Found: C, 72.83; H, 8.39; N, 8.88.

NMR (300 MHZ, CDCl₃): δ0.91 (triplet, 6H); 1.49 (sextet, 4H); 2.58(sextet, 4H); 2.78 (triplet, 1H); 3.00 (quartet, 1H); 3.03 (triplet,1H); 3.23 (multiplet, 1H); 3.81 (quartet, 1H); 3.91 (singlet, 3H); 6.88(singlet, 1H); 7.14 (doublet, 1H); 7.84 (doublet, 1H); 8.02 (singlet,1H).

Preparation Example 12(±)-4-(Di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, ethyl ester

A. (+)-1-Ethoxycarbonyl-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, ethyl ester

A solution of 0.335 g (1 mmol) of4-(di-n-propylamino)-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole in 5 mlof diethyl ether was added to a suspension of 0.19 g (1.2 mmol) ofpotassium hydride in a 25% by weight mineral oil dispersion in 25 ml ofdiethyl ether at about 0° C. The reaction mixture was stirred at 0° C.for 1 hour and cooled to about -78° C. with an external dry ice/acetonebath. A solution of 1.7M t-butyllithium (1.5 ml, 2.55 ml ) cooled to-78° C. was added to the reaction mixture via a cannula. The resultingmixture was allowed to warm to about -40° C. and held there for 2 hours.The resulting turbid mixture was cooled to about -78° C. To this mixturewas added a solution of 0.4 g (4 mmol) of ethyl cyanoformate in 1 ml ofdiethyl ether. The reaction mixture was warmed to about 0° C. andquenched with ice water. The mixture was washed with diethyl ether andthe ether extract was extracted with 1M phosphoric acid. The aqueoussolutions were combined and treated with an aqueous sodium bicarbonatesolution and extracted with methylene chloride. The methylene chlorideextract was dried over anhydrous sodium sulfate and concentrated undervacuum to provide 0.44 g of a residue. The residue was chromatographedover 5 g of silica gel using ethyl acetate:toluene (1:9, v:v) as theeluant. Fractions containing the major component were combined and thesolvent was evaporated therefrom to provide 164 mg of the desiredcompound(±)-1-ethoxycarbonyl-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6carboxylicacid, ethyl ester.

B. A solution of 164 mg (0.41 mmol) of(±)-1-ethoxycarbonyl-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxylicacid, ethyl ester in 10 ml of methanol was added slowly to a solution of2.0 g of potassium carbonate in 10 ml of water and 20 ml of methanol.The reaction mixture was stirred at room temperature for approximately 1hour and diluted with an aqueous sodium chloride solution and extractedwith methylene chloride. The organic extracts were combined, dried overanhydrous sodium sulfate and concentrated under vacuum to provide 149 mgof residue. The residue was recrystallized from toluene/hexane toprovide 165 mg of(±)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz-[c,d]-6-carboxylic acid,ethyl ester. mp=116.5°-117° C.

Analysis calculated for C₂₀ H₂₈ N₂ O₂ Theory: C, 73.14; H, 8.59; N,8.53; Found: C, 72.86; H, 8.77; N, 8.54.

NMR (300 MHz, CDCl₃): δ0.91 (triplet, 6H); 1.42 (triplet, 3H); 1.49(sextet, 4H); 2.58 (triplet, 4H); 2.78 (triplet, 1H); 3.00 (quartet,1H); 3.03 (triplet, 1H); 3.23 (multiplet, 1H,); 3.83 (quartet, 1H); 4.36(multiplet, 2H); 6.88 (singlet, 1H); 7.14 (doublet, 1H); 7.84 (doublet,1H); 8.04 (singlet, 1H).

Preparation Example 13(±)-4-(Dimethylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxaldehyde

To a suspension of 0.9 g (3.96 mmol) of(±)-4-(dimethylamino)-6-cyano-1,3,4,5-tetrahydrobenz[c,d]indole in 10 mlof benzene stirred at room temperature under a nitrogen atmosphere wasadded 8.1 ml (8.1 mmol) of 1M diisobutylaluminum hydride in toluenedropwise. The reaction mixture was stirred at about 50° C. for 6 hours.The mixture was cooled to room temperature and a solution of 1.0 ml ofmethanol in 4.5 ml of toluene was added to dissolve the precipitate thathad formed. Next, 1.0 ml of water in 4.5 ml of methanol was added, andthe resulting mixture was added to ice cold 0.5M hydrochloric acid andshaken. The aqueous layer and a 0.5M hydrochloric acid extraction of theseparated organic phase were combined and made basic with 2M sodiumhydroxide. The aqueous phase was extracted with methylene chloride, andthe organic phase was washed with a saturated sodium chloride solution,dried over anhydrous sodium sulfate and concentrated under vacuum toprovide an oil. The oil was chromatographed employing ethylacetate:methanol (19:1, v:v) as the eluant. Fractions containing themajor component were combined and the solvent was evaporated therefromto provide 0.5 g of the title compound following recrystallization fromethyl acetate/toluene. mp=163° C.

Analysis calculated for C₁₄ H₁₆ N₂ O Theory: C, 73.66; H, 7.06; N,12.27; Found: C, 73.50; H, 7.02; N, 12.17.

NMR (300 MHz, CDCl₃): δ2.48 (singlet, 6H); 2.86 (quartet, 1H); 3.08(multiplet, 2H); 3.19 (multiplet, 1H); 3.86 (broad doublet, 1H); 6.95(singlet, 1H); 7.25 (doublet, 1H); 7.66 (doublet, 1H); 8.31 (singlet,1H); 10.28 (singlet, 1H).

Preparation Example 14(±)-4-(Di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]-indole-6-carboxaldehyde

A 100 ml three neck round bottom flask under a nitrogen atmosphere wascharged with 0.176 g (1.1 mmol) of 25% potassium hydride in mineral oilwhich had been washed with heptane. To the flask was added 40 ml ofdiethyl ether and the mixture was cooled to about 0° C. To the mixturewas added a solution of 0.335 g (1.0 mmol) of(±)-4-(di-n-propylamino)-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole in 10ml of diethyl ether over a period of about 5 minutes. The mixture wasstirred at about 0° C. for one hour, and for three hours at roomtemperature. The mixture was cooled to about -78° C. with an externaldry ice/acetone bath and 1.47 ml of 1.7M t-butyllithium was addeddropwise over a period of about 10 minutes. The mixture was warmed toabout -50° C. over about two hours. The mixture was again cooled toabout -78° C. and 0.193 ml of dry DMF in 10 ml of diethyl ether wasadded. The mixture was stirred at -78° C. for 30 minutes, warmed to roomtemperature, and stirred overnight. To the mixture was added 50 ml ofwater and 25 ml of diethyl ether. The mixture was washed twice with 50ml portions of water. The organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to provide 0.17 g of abrown oil. The oil was chromatographed over silica gel employing ethylacetate: toluene:triethylamine (42:42:16, v:v:v) as the eluant.Fractions containing the major component were combined and the solventwas evaporated therefrom to provide 0.19 g of(±)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole-6-carboxaldehydeas a yellow oil.

NMR (300 MHz, CDCl₃): δ0.95 (triplet, 6H); 1.50 (multiplet, 4H); 2.60(triplet, 4H); 3.10 (multiplet, 4H); 3.80 (doublet, 1H); 7.00(multiplet,3H); 8.3 (singlet, 1H); 10.3 (singlet, 1H).

Nonendogenous Indoles

A third class of direct acting 5-HT1A agonists comprises nonendogenousindole derivatives or a pharmaceutically acceptable acid addition saltthereof. These indole derivatives include various 3-substituted indoles,5-substituted indoles and 3-substituted-5substituted indoles. Examplesof such indoles are described in Middlemiss, Annual Reports of MedicinalChemistry, 21, 41-50 (Academic Press, 1986). Further examples of theseindoles are described in Fuller, Monographs in Neural Sciences, 10,158-181 (Karger, Basel, Switzerland 1984).

Illustrative examples of such compounds includes:

5-methoxytryptamine;

5-aminocarbonoyltryptamine;

5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-indole;

N,N-di-n-propyl-5-carbamoyltryptamine;

N,N-dimethyl-5-methoxytryptamine;

N,N-diethyl-5-methoxytryptamine;

N,N-di-n-propyl-5-methoxytryptamine;

5-methoxy-3-[2-[1-(4-phenyl)-1,2,3,6-tetrahydropyridyl]ethyl]indole;

N,N-dimethyl-5-hydroxytryptamine;

N,N-dimethyltryptamine; and

N,N-dipropyl-5-hydroxytryptamine

These compounds are prepared according to Glennon et. al., J. Med.Chem., 31, 867-870 (1988) or Taylor et. al., Molecular Pharmacology, 34,42 (1988) which are both incorporated by reference herein in theirentirety.

At least 5-methoxytryptamine; N,N-dimethyl-5-methoxytryptamine;N,N-dimethyl-5-hydroxytryptamine; and N,N-dimethyltryptamine arecommercially available from sources such as Aldrich Chemical Company,Inc., 940 West Saint Paul Avenue, Milwaukee, Wis. 53233 U.S.A., SigmaChemical Company, P.O. Box 14508, St. Louis, Mo. 63178 U.S.A.; or both.References to the preparation of N,N-dimethlytryptamine and5-methoxytryptamine are provided in The Merck Index, 10th ed., Merck &Co., Inc. (1983).

As mentioned above, useful compounds for practicing the method of thepresent invention includes pharmaceutically acceptable acid additionsalts of the nonendogenous indole derivative compounds. Since thesecompounds are amines, they are basic in nature and accordingly reactwith any of a number of inorganic and organic acids to formpharmaceutically acceptable acid addition salts. Acids commonly employedto form such salts are inorganic acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, andthe like, and organic acids such as p-toluenesulfonic, methanesulfonicacid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinicacid, citric acid, benzoic acid, acetic acid, and the like. Examples ofsuch pharmaceutically acceptable salts thus are the sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexynel,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,γ-hydroxybutyrate, glycollate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate, and the like. Preferred pharmaceutically acceptable acidaddition salts are those formed with mineral acids such as hydrochloricacid and hydrobromic acid, and those formed with organic acids such asmaleic acid.

In addition, some of these salts may form solvates with water or organicsolvents such as ethanol. Such solvates also are included within thescope of this invention.

Among the 5-HT1A agonist compounds included in this class as describedabove, including those compounds described in references that have beenincorporated by reference, certain of these compounds are preferred. Thepreferred compounds are 5-methoxy-3-(1,2,3,6,-tetrahydropyridine-4-yl)indole; N,N-dipropyl-5-methoxytryptamine; andN,N-dipropyl-5-carboxamidotryptamine.

The compounds employed as initial starting materials in the synthesis ofthe indole compounds of this class are well known and readilysynthesized by standard procedures commonly employed by those ofordinary skill in the art.

The pharmaceutically acceptable salt addition salts are typically formedby reacting a 3-substituted, 5-substituted or3-substituted-5-substituted indole with an equimolar or excess amount ofacid. The reactants are generally combined in a mutual solvent such asdiethyl ether or benzene, and the salt normally precipitates out ofsolution within about one hour to 10 days, and can be isolated byfiltration.

Aryloxypropanolamines

A fourth class of compounds acting at the 5-HT1A receptor comprises aseries of aryloxypropanolamines. These compounds have the Formula##STR12## where Ar is an optionally mono- or disubstituted phenyl ornaphthalene ring where the substituents are selected from allyl, C₁ -C₄alkyl, O(C₁ -C₄ alkyl), -(C₁ -C₄ alkylidene)-O-(C₁ -C₄ alkyl), O-allyl,CN, NHCO(C₁ -C₃ alkyl), --CH₂ CONH₂, trifluoromethyl, hydroxy, halo, (C₁-C₄ alkyl)-S(O)_(p) --, where p is 0, 1, or 2 and a C₃ -C₈ cycloalkyl ora bicycloalkyl group of the Formula; ##STR13## where a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; and G' is abond or C₁ -C₄ alkylidene; or where Ar is the group. ##STR14## Z is astraight or branched C₃ -C₁₀ alkyl; C₄ -C₁₀ alkenyl; C₄ -C₁₀ alkynylgroup; a phenyl(C₂ -C₁₀) alkyl where the phenyl moiety may besubstituted with a halo, C₁ -C₄ alkyl, trifluoromethyl, hydroxy, C₁ -C₄alkoxy, C₁ -C₄ alkyl-S(O)_(p) -- where p is 0, 1, or 2; a group G-Vwhere G is independently a bond or C₁ -C₄ alkyl or phenyl, and V is C₄-C₈ cycloalkyl optionally substituted with a C₁ -C₄ alkyl or phenyl; a-(C₁ -C₄ alkylidene)-T-(C₁ -C₄ ALKYL) where T is --O--, --S--, --SO--,or --SO₂ --; or a bicycloalkyl group having the Formula ##STR15## whereG is as defined above and a and c are independently 1-5, b is 0-5, and(a+c) is greater than 2; R¹⁰ is an optional methyl group substituted onone of the three connecting carbon atoms; or a pharmaceuticallyacceptable salt thereof.

Preferred aryloxypropanolamines have the Formula ##STR16## where Ar is##STR17## R¹⁰ is an optional methyl group substituted on one of thethree connecting carbon atoms;

R¹¹ is hydrogen, C₁ -C₄ alkyl, trifluoromethyl, hydroxy, halo, (C₁ -C₄alkyl)-O--, (C₁ -C₄ alkyl)-S(O)_(p) --, where p is 0, 1, or 2; R¹² is C₃-C₈ cycloalkyl or a bicycloalkyl group of the Formula: ##STR18## where aand c are independently 1-5, b is 0-5, and (a+c) is greater than 2; Z isa straight or branched C₄ -C₁₀ alkyl, alkenyl, or alkynyl group, (C₄ -C₈cycloalkyl)-G- optionally substituted with C₁ -C₄ alkyl or phenyl, abicycloalkyl group of the Formula: ##STR19## wherein a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2, optionallysubstituted phen (C₂ -C₁₀) alkyl where the phenyl group can besubstituted with R¹¹ as previously defined, or -(C₁ -C₄alkylidene)-T-(C₁ -C₄ alkyl), where T is --O--, --S--, --SO--, or --SO₂--; where each G is independently a bond or C₁ -C₄ alkylidene; or apharmaceutically-acceptable salt thereof.

Although it is generally proposed that these compounds antagonizecentral 5-HT1A and 5-HT1B receptors, it has been discovered that thesecompounds are partial 5-HT1A agonists. As shown below, these compoundsare effective inhibitors of gastric acid secretion.

The term "C₁ -C₄ alkyl" refers to methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, t-butyl, and isobutyl. The term "C₄ -C₈ cycloalkyl"refers to cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Optional substituents on the C₅ -C₈ cycloalkyl ring maybe atany position or orientation on the ring other than at the point ofattachment to the nitrogen atom.

The term "straight or branched C₄ -C₁₀ alkyl" includes alkyl groups of4-10 carbon atoms as either straight-chain hydrocarbons or with one ormore points of branching. Similarly, the term "straight or branched C₄-C₁₀ alkenyl or alkynyl group" refers to similar straight or branchedhydrocarbon chains containing a double or triple bond, respectively."Halo" refers to fluoro, chloro, bromo, and iodo.

The term "-(C₁ -C₄ alkylidene)-T-(C₁ -C₄ alkyl)" refers to two straightor branched C₁ -C₄ alkyl groups bridged by the T functionality. The term"C₁ -C₄ alkylidene" refers to a divalent radical derived from a C₁ -C₄alkane.

The bicycloalkyl groups defined as part of the R¹² and Z substituentsinclude bicyclic rings of four to seventeen carbon atoms. Thesebicycloalkyl groups include bridged and fused two-ring systems.

The R¹⁰ optional methyl group is one wherein the three-carbon bridgebetween the aryloxy and amine functionalities are optionally substitutedwith a methyl group. That is, in addition to the --CH₂ CH(OH)CH₂ --bridge as drawn in Formula III, such bridging groups also include--CH(CH₃)CH(OH)CH₂ --, --CH₂ C(OH)(CH₃)CH₂ --, and --CH₂CH(OH)CH(CH₃)--.

It is recognized that depending upon the R.sup.° , hydroxy, and Zsubstituent groups, one or more steroisomers and/or enantiomers arepossible. This invention is not limited to any particular isomer butincludes all possible individual isomers and all combinations thereof.

The pharmaceutically acceptable addition salts employed in thisinvention include salts derived from inorganic acids such ashydrochloric acid, nitric acid, phosphoric acid, sulfuric acid,hydrobromic acid, hydriodic acid, phosphorus acid, and the like, as wellas salts derived from organic acids, such as aliphatic mono- ordi-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoicand -alkandioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, and the like.

Most preferred aryloxypropanolamines are represented by the FormulaIIIB. ##STR20## where m is 0-3, especially 2, and Z is (C₆ -C₈cycloalkyl)-G-, C₆ -C₁₀ alkyl, phenyl (C₂ -C₁₀) alkyl, -(C₁ -C₄alkylidene)-T-(C₁ -C₄ alkyl), or ##STR21## where unless otherwisestated, the variables are as previously defined, or a pharmaceuticallyacceptable salt thereof.

The compounds employed in the method of this invention are known in theart or can be prepared by methods known in the art. A referenceillustrative of this chemistry includes U.S. Pat. No. 3,551,493(penbutolol and derivatives) and EPA 345,056, which are expresslyincorporated by reference herein in their entirety.

In general, the compounds are best prepared according to the followingScheme: ##STR22##

According to this Scheme, the hydroxy aromatic intermediate is reactedwith epichlorohydrin or a halo congener thereof to provide thearyloxy-epoxy derivative. This chemistry is well established in the artand can be conducted in a number of ways, generally employing an inertsolvent and a nonreactive acid scavenger. The aryloxy-epoxide is thenreacted with a primary amine H₂ NZ to provide the compounds of FormulaIII. Once again, the reaction is usually performed in the presence of anonreactive solvent and at elevated temperatures up to the refluxtemperature of the reaction mixture. Scheme I is drawn contemplatingthose compounds wherein R¹⁰ is hydrogen; by employing the appropriatelysubstituted epihalohydrin, the other compounds of Formula III may beprepared in a similar manner. The pharmaceutically acceptable salts ofFormula III compounds are also be prepared by standard methods known tothose skilled in this art.

Preparation Example 151-(2-cyclopeutylphenoxy)-3-(cyclohexylamino)-2-propanol ethanedioate

A mixture of 3.17 g of 3-(2-cyclopentylphenoxy)-1,2-epoxypropane and2.01 g of cyclohexylamine were heated to reflux in methanol overnight.The mixture was cooled, concentrated in vacuo, diluted with ethylacetate and treated with a solution of oxalic acid in ethyl acetate. Theresulting precipitate was recovered by filtration and crystallized fromethyl acetate/diethyl ether to afford 77% yield of the title product,m.p. 214°-215° C.

The following compounds are prepared in similar fashion from theappropriate aryloxyepoxypropane and corresponding amine:

1-(2-Cyclopentylphenoxy)-3-(cycloheptylamino)-2-propanol ethanedioate,47% yield, m.p. 192°-194° C.

1-(2-Cyclopentylphenoxy)-3-(cyclooctylamino)-2-propanol ethanedioate,10% yield;

1-(2-Cyclopentylphenoxy)-3-(2,2-dimethyl-3-butylamino)-propanolethanedioate, 9% yield;

1-(2-Cyclopentylphenoxy)-3-(1,1-dimethylbutylamino)-2-propanolethanedioate, 21% yield;

1-(2-Cyclopentylphenoxy)-3-(myrtanylamino)-2-propanol ethanedioate;

1-(2-Cyclopentylphenoxy)-3-(Cyclopentylamino)-2-propanol ethanedioate;

1-(2-cyclohexylphenoxy)-3-(tert-butylamino)-2-propanol ethandioate.

Benzodioxanes

A fifth class of direct acing 5-HT1A agonists comprises benzodioxaneanalogues having the Formula ##STR23## where X⁶ is hydrogen, hydroxy, or--O(C₁ -C₃)alkyl;

R¹⁵ is hydrogen; and

R¹⁶ is --(CH₂)_(d) --Y² --Z¹ where d is 2-4;

Y² is a bond, --O-- or --S--; and

Z¹ is unsubstituted, mono- or disubstituted phenyl where thesubstituents are selected from halo, trifluoromethyl, C₁ -C₃ alkyl, C₁-C₃ alkoxy, or C₁ -C₃ alkylthio; C₃ -C₆ cycloalkyl group or a8-azaspiro[4,5]-decan-7,9-dione group; or NR¹⁵ R¹⁶ comprises a8-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one) group; or apharmaceutically acceptable salt thereof.

Specific examples of members of this class include2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane, spiroxatrine;2-[(3-Cyclohexylpropyl)aminomethyl]-8-hydroxy-1,4-benzodioxane;2-[2-(3,4-dimethoxyphenyl)ethyl]aminomethyl-1,4-benzodioxane;2-[(2-phenylethyl)aminomethyl]-8-ethoxy-1,4-benzodioxane;2-[(2-phenylethyl)aminomethyl]-1,4-benzodioxane;4-oxo-1-phenyl-8-(1,4-benzodioxan-2-ylmethyl)-1,3,8-triazaspiro[4.5]decane;and8-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]-8-azaspiro[4.5]decane-7,9-dione.

In the above Formula IV, the term "halo" means any of fluoro, chloro,bromo and iodo. The term C₁ -C₃ alkyl" by itself or as part of an alkoxyor alkylthio group means methyl, ethyl, n-propyl, and isopropyl.

As mentioned hereinabove, useful compounds for practicing the method ofthe present invention includes pharmaceutically acceptable salts of thecompounds defined by the above Formula IV Since these compounds areamines, they are basic in nature and accordingly react with any of anumber of inorganic and organic acids to form pharmaceuticallyacceptable acid addition salts. Since the free amines of these compoundsare typically oils at room temperature, it is preferable to convert thefree amines to their corresponding pharmaceutically acceptable acidaddition salts for ease of handling and administration, since the latterare routinely solid at room temperature. Acids commonly employed to formsuch salts are inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, andorganic acids such as p-toluenesulfonic, methanesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexynel,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, madelate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid.

In addition, some of these salts may form solvates with water or organicsolvents such as ethanol. Such solvates also are included within thescope of this invention.

These compounds are prepared by alkylation of the appropriate amine withthe corresponding halomethylbenzodioxane according to the followingreaction: ##STR24##

Further details regarding preparation of the benzodioxanes of FormulaIV, including preparation of the halomethylbenzodioxanes reactant aredescribed in U.S. Pat. Nos. 2,906,757 and 2,922,744 both of which areincorporated herein by reference in their entirety. When X⁶ is hydrogen,2-hydroxymethyl-1,4-benzodioxane can be used to prepare thecorresponding halomethyl reactant by procedures well known to thoseskilled in the art. The 2-hydroxymethyl-1,4-benzodioxane compound iscommercially available from Aldrich Chemical Co.

Alternatively, for those compounds where X⁶ is hydrogen J. Med. Chem.,20, 880 (1977) discloses a method for the synthesis of either2-tosyloxymethyl enantiomers. This compound is then converted to theprimary 2-aminomethyl compound using conditions substantially similar tothose described in J. Med. Chem., 8, 446 (1965) for the correspondingbromide. Both of these J. Med. Chem. articles are incorporated byreference herein in their entirety.

Those compounds where R.sup.≠ is --(CH₂)_(d) --Y² --Z¹ where d is 2-4,Y² is a bond and Z¹ is 8-azaspiro[4,5]-decan-7,9-dione group areprepared according to procedures described in EPA 170,213 and Hibert et.al., J. Med. Chem., 31, 1087-1093 (1988) which are both incorporated byreference herein in their entirety.

The amino reactant to the extent not commercially available, is preparedfrom commercially available materials using known procedures.

The pharmaceutically acceptable salts of the compounds of Formula IV areprepared using procedures well known to those skilled in the art.

Phenylcyclopropylamines

A sixth class of direct acting 5-HT1A agonists comprises2-phenyl-N,N-dialkylcyclopropylamines having the Formula ##STR25## whereR¹³ is C₁ -C₃ alkyl;

X³ is hydrogen, OH or OCH₃ ;

Y is hydrogen, OH or OCH₃ ; and pharmaceutically acceptable saltsthereof provided that one of X³ and Y must be hydrogen.

It is recognized that these compounds exist in two enantiomeric forms.This invention is not limited to any particular isomer, but includesboth individual enantiomers and mixtures thereof.

As mentioned above, useful compounds for practicing the method of thepresent invention includes pharmaceutically acceptable salts of thecompounds defined by the above Formula. Since these are amines, they arebasic in nature and accordingly react with any of a number of inorganicand organic acids to form pharmaceutically acceptable acid additionsalts. Acids commonly employed to form such salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexynel,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, madelate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid.

In addition, some of these salts may form solvates with water or organicsolvents such as ethanol. Such solyates also are included within thescope of this invention.

Representative examples of these compounds includes:

2-(2-hydroxyphenyl)-N,N-di-n-propyl-cyclopropylamine;

2-(3-hydroxyphenyl)-N,N-di-n-propyl-cyclopropylamine;

2-(2-methoxyphenyl)-N,N-di-n-propyl-cyclopropylamine;

2-(3-methoxyphenyl)-N,N-di-n-propyl-cyclopropylamine;

2-(2-hydroxyphenyl)-N,N-diethyl-cyclopropylamine;

2-(3-hydroxyphenyl)-N,N-diethyl-cyclopropylamine;

2-(2-methoxyphenyl)-N,N-diethyl-cyclopropylamine;

2-(3-methoxyphenyl)-N,N-diethyl-cyclopropylamine;

2-(2-hydroxyphenyl)-N,N-dimethyl-cyclopropylamine; and

2-(3-hydroxyphenyl)-N,N-dimethly-cycloproplyamine.

The 2-(phenyl)-N,N-dialkylcyclopropylamines of the above Formula V areprepared according to procedures described in Arvidsson et. al., J. Med.Chem., 31, 92-99 (1988) which is incorporated by reference herein in itsentirety.

The optically active isomers of the reacemates of the compounds ofFormula IV are also considered within the scope of compounds useful inproviding the method of the present invention. Such optically activeisomers are prepared from their respective optically active precursorsby the procedures described in Arvidsson et. at., J. Med. Chem., 31,92-99 (1988), or by resolving the racemic mixtures. It is believed thisresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization. Useful resolving agentsinclude d- and l-tartaric acids, d- and l-ditoluoyltartaric acids, andthe like.

The compounds employed as initial starting materials in the synthesis ofthe compounds of this invention are well known and commerciallyavailable or readily synthesized by standard procedures commonlyemployed by those of ordinary skill in the art.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a 2-(phenyl)-N,N-dialkyl-cyclopropylamine of Formula V withan equimolar or excess amount of acid. The reactants are generallycombined in a mutual solvent such as diethyl ether or benzene, and thesalt normally precipitates out of solution within about one hour to 10days, and can be isolated by filtration.

N-Arylpiperazines

A seventh class of direct acting 5-HT1A agonists comprisesN-arylpiperazine derivates or a pharmaceutically acceptable saltthereof. Representative examples of compounds within this class includethose disclosed in U.S. Pat. No. 4,818,756, which describes substituted2-pyrimidinyl-1-piperazine derivatives and defines those derivativeswith greater particularly. U.S. Pat. No. 4,818,756, which isincorporated by reference herein in its entirety, also discloses methodsfor preparing those compounds.

Further examples of compounds within this class include those disclosedin EPA 082 402 which describes succinimide derivatives substituted withpiperazinylalkyl group at the imido nitrogen atom. EPA 082 402, which isincorporated by reference herein in its entirety, discloses methods forpreparing those compounds.

Still further examples of 5-HT1A agonist compounds within this class aredisclosed in J. Med. Chem., 15, 477 (1972); J. Med. Chem., 26, 194(1983); and J. Med. Chem., 31, 1382 (1988) which are all incorporated byreference herein in their entirety. These three references also describemethods for preparing those compounds.

The N-arylpiperazines may be further substituted by a8-azospiro[4,5]decane-7 9-dione; 4,4-dimethyl-2,6-piperidinedione;benzisothiazole-3(2H)-one-1,1-dioxide; 3aα, 4a, 5, 6,7aα-hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione; phenyl,substituted phenyl where the substituents are selected from halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, amino, acetamido, 2-haloacetamido, andtrifluoromethyl, where said further substituent is bonded to the othernitrogen atom of the N-arylpiperazine by a C₁ -C₄ alkylene bridge.

As used for this class of compounds, "halogen" and "halo" should beunderstood as chloro, bromo, fluoro, and iodo.

The N-arylpiperazines described in the above references and within thescope of the present invention are 5-HT1A agonists having the Formula:##STR26## where Ar¹ is 2-pyrimidinyl; phenyl or substituted phenyl wherethe substituent is selected from halo; C₁ -C₄ alkyl, C₁ -C₄ alkoxy, andCF₃ ;

R¹⁸ is hydrogen or --(CH₂)_(q) --Ar² where q is 1 to 4; and

Ar² is phenyl, substituted phenyl where the substituent is selected fromhalo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, NHC(O)CH₃, NHC(O)CH₂ Cl or CF₃ ;or Ar² is a group selected from groups having the Formulae: ##STR27## ora pharmaceutically acceptable salt thereof.

As mentioned above, useful compounds for practicing the method of thepresent invention includes pharmaceutically acceptable acid additionsalts of the arylpiperazines compounds. Since these compounds areamines, they are basic in nature and accordingly react with any of anumber of inorganic and organic acids to form pharmaceuticallyacceptable acid addition salts. Acids commonly employed to form suchsalts are inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, phosphoric acid, and the like, andorganic acids such as p-toluenesulfonic, methanesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and citric acid.

In addition, some of these salts may form solvates with water or organicsolvents such as ethanol. Such solvates also are included within thescope of this invention.

Representative examples of these compounds includes8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]8-azaspiro[4.5]decane-7,9-dione(buspirone);4,4-di-methyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6-piperidinedione(gepirone);2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]benzisothiazole-3(2H)-one1,1-dioxide (ipsapirone); 1-(3-trifluoromethylphenyl)piperazine;1-(3-trifluoromethylphenyl)-4-[2-(4-aminophenyl)ethyl]piperazine (PAPP);1-(3-trifluoromethylphenyl)-4-[2-[3(2-bromoacetamido)phenyl]ethyl]piperazine;1-(3-trifluoromethylphenyl)-4-[2-[3-(2-chloroacetamido)phenyl]ethyl]piperazine;and (3aα, 4α, 5, 6, 7α,7aα)-hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione.

The N-arylpiperazine compounds are prepared by procedures described inU.S. Pat. No. 4,518,756 and EPA 082 402, which have both beenincorporated by reference herein, or other procedures well-known tothose of ordinary skill in the art.

For example,8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane isprepared by the condensation of 1-(2-pyrimidinyl)piperazine with3-chloro-1-cyanopropane by means of Na₂ CO₃ in n-butanol gives4-(2-pyrimidinyl)-1-(3-cyanopropyl)piperazine which is reduced withLiA1H₄ or with H₂ and Raney nickel (RaNi) yielding4-(2-pyrimidinyl)-1-(4-aminobutyl)piperazine, which is finally condensedwith 8-oxaspiro[4,5]-decane-7,9-dione(3,3-tetramethyleneglutaricanhydride) in pyridine.

The preparation of4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6-piperidinedioneproceeds by preparing the quaternary salt from1-(pyrimidin-2-yl)piperazine and 1,4-dibromobutane which then undergoesreaction with 3,3-dimethylglutarimide in the presence of potassiumcarbonate in refluxing xylene to afford the free base which is isolatedby acid extraction and basification of the extract. Treatment of thefree base with HCl in isopropanol affords the compound as themonohydrochloride salt.

The compound2-[4-[4-(2-pyrimidinyl)piperazinyl]butyl]benzoisothiazole-3(2H)-one1,1-dioxide is prepared by the reaction of benzoisothiazole-3(2H)-one1,1-dioxide with 1,4-dibromobutane by means of NaH in DMF to afford2-(4-bromobutyl)benzoisothiazole-3(2H)-one 1,1-dioxide which is thencondensed with 1-(2-pyrimidinyl)piperazine by means of K₂ CO₃ inrefluxing chlorobenzene.

The compound3aα,4α,5,6,7,7aα)-hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dioneprepared by the condensation of norbornane-2,3-di-endocarboxylicanhydride with 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in refluxingpyridine.

Starting materials for these preparations, to the extent notcommercially available are prepared by methods well known to thoseskilled in the art.

Further preparation information on the N-arylpiperazines is set forth inYevich et. al., J. Med. Chem., 26, (2), 194-203 (1983); Wu et al., J.Med. Chem., 15, (5), 477-479 (1972); and Wu et al., J. Med. Chem., 12,876-881 (1969) which are incorporated by reference herein in theirentirety.

Piperidinylmethyl Tetrahydroisoquinolines

An eighth class of direct acting 5-HT1A agonists comprises2-(4-piperidinylmethyl)-1,2,3,4-tetrahydroisoquinolines having theFormula: ##STR28## where

R¹⁷ is hydrogen; C₁ -C₆ alkyl; allyl; (C₃ -C₆ cycloalkyl)methyl; benzylwhere the ring is optionally substituted with 1, 2, or 3 substituentsselected from halo, CF₃, NO₂, NH₂, N(CH₃)₂, CN, CONH₂, C₁ -C₃ alkyl, C₁-C₃ alkoxy and C₁ -C₃ alkylthio; 2-phenylethyl; 3-phenylpropyl;3-phenylpropen-2-yl; phenylcarbonylmethyl; naphthylmethyl;pyridylmethyl; furanylmethyl; thienylmethyl; C₂ -C₆ alkanoyl; C₃ -C₆cycloalkylcarbonyl; CF₃ CO; phenylcarbonyl optionally ring substitutedwith 1, 2, or 3 substituents selected from halo, NO₂, CF₃, C₁ -C₃ alkyl,C₁ -C₃ alkoxy and C₁ -C₃ alkylthio; 1-oxo-3-phenylpropen-2-yl;naphthylcarbonyl; pyridinylcarbonyl; furancarbonyl; thienylcarbonyl; or2- or 5-indolylcarbonyl or a pharmaceutically acceptable salt thereof.

This class of compounds and methods for their preparation are disclosedin EPA 306375 which is incorporated by reference herein in its entirety.

As used for this eighth class of compounds "alkyl" by itself or as partof another moiety means, unless otherwise stated a straight or branchedchain group having the stated number of carbon atoms. Representativeexamples include methyl, ethyl, n-propyl, isopropyl and higher homologsand isomers where stated. "Halo" means fluoro, chloro, bromo or iodo.

As mentioned above, useful compounds for practicing the method of thepresent invention includes pharmaceutically acceptable salts of thecompounds. Since these compounds are amines, they are basic in natureand accordingly react with any of a number of inorganic and organicacids to form pharmaceutically acceptable acid addition salts. Acidscommonly employed to form such salts are inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexynel, 6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzohydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, madelate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid.

In addition, some of these salts may form solvates with water or organicsolvents such as ethanol. Such solyates also are included within thescope of this invention.

The present invention provides a method of inhibiting gastric acidsecretion in mammals, preferably humans, comprising administering to amammal in need of of gastric acid secretion inhibition an effective doseof a direct acting 5-HT1A receptor agonist, or a pharmaceuticallyacceptable salt thereof.

By the term "effective dose" is meant an amount of a 5-HT1A agonist, ora pharmaceutically acceptable salt thereof, which will inhibit fromabout one percent to about 99 percent of the volume of gastric acidsecreted or inhibit the acidity of gastric secretion by a pH value offrom about 0.1 to about 5.0, or inhibit both the volume and acidity ofgastric secretion within said parameters. The gastric acid secretioninhibition contemplated by the present method includes both medicaltherapeutic and/or prophylactic treatment, as appropriate. The specificdose of a particular compound, or pharmaceutically acceptable saltthereof, administered according to this invention will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration, and the condition being treated. A typical daily dosewill generally contain from about 0.01 mg/kg to about 20 mg/kg of adirect acting 5-HT1A agonist or a pharmaceutically acceptable saltthereof. Preferred daily doses generally will be from about 0.05 toabout 10 mg/kg and more preferrably from about 0.1 to about 5 mg/kg.

The compounds useful in practicing the method of this invention arepreferably formulated prior to administration. Such a pharmaceuticalformulation comprises a 5-HT1A against compound or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier,diluent or excipient therefor.

The active ingredient in such formulations comprises from about 0.1% toabout 99% by weight of the formulation. By "pharmaceutically acceptable"is meant the carrier, diluent or excipient must be compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

The present pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be asolid, semisolid or liquid material which acts as a vehicle, excipientor medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, sterile packaged powders,and the like.

Examples of suitable carriers, excipients, and diluents are lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methylhydroxybenzoates, propylhydroxybenzoates, talc, magnesium stearate, and mineral oil. Theformulations may additionally include lubricating agents, wettingagents, emulsifying agents, suspending agents, preserving agents,sweetening agents, flavoring agents, and the like. The compositions ofthe invention may be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage generally containing from about 0.1 to about 500 mg, andpreferably from about 1 to about 250 mg, of the active ingredient. Theterm "unit dosage form" refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic and/or prophylactic effect, inassociation with a suitable pharmaceutical carrier.

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way. "Activeingredient", of course, means a direct acting 5-HT1A agonist or apharmaceutically acceptable salt thereof as described herein.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                       Quantity                                                                      (mg/capsule)                                                   ______________________________________                                        Active ingredient                                                                              250                                                          starch, dried    200                                                          magnesium stearate                                                                             10                                                           Total            460         mg                                               ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                         Quantity                                                                      (mg/tablet)                                                  ______________________________________                                        Active Ingredient  250                                                        cellulose, microcrystalline                                                                      400                                                        silicon dioxide, fumed                                                                           10                                                         stearic acid       5                                                          Total              665        mg                                              ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 3

An aerosol solution is prepared containing the following components:

    ______________________________________                                                        Weight %                                                      ______________________________________                                        Active Ingredient 0.25                                                        ethanol           29.75                                                       Propellant 22     70.00                                                       (chlorodifluoromethane)                                                       Total             100.00                                                      ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient       60     mg                                             starch                  45     mg                                             microcrystalline cellulose                                                                            35     mg                                             polyvinylpyrrolidone    4      mg                                             (as 10% solution in water)                                                    sodium carboxymethyl starch                                                                           4.5    mg                                             magnesium stearate      0.5    mg                                             talc                    1      mg                                             Total                   150    mg                                             ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 60 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient       80     mg                                             starch                  59     mg                                             microcrystalline cellulose                                                                            59     mg                                             magnesium stearate      2      mg                                             Total                   200    mg                                             ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient       225    mg                                             saturated fatty acid glycerides                                                                       2,000  mg                                             Total                   2,225  mg                                             ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of active ingredient per 5 ml dose,are made as follows:

    ______________________________________                                        Active ingredient        50     mg                                            sodium carboxymethyl cellulose                                                                         50     mg                                            syrup                    1.25   ml                                            benzoic acid solution    0.10   ml                                            flavor               q.v.                                                     color                q.v.                                                     purified water to total  5      ml                                            ______________________________________                                    

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows:

    ______________________________________                                        Active ingredient     100    mg                                               isotonic saline       1000   ml                                               ______________________________________                                    

The solution of the above ingredients generally is administeredintravenously at a rate of 1 ml per minute to a subject in need of theinhibition of gastric acid secretion.

The gastric acid inhibition activity of direct acting 5-HT1A agonistswas established by evaluations using the pylorus ligated rat model. Inthe pylorus ligated rat model, changes in basal acid secretion mayreflect a stimulatory or inhibitory action depending on treatment ofcompound type tested. The compounds tested were confirmed by variousreceptor binding tests to have an affinity for the 5-HT1A receptor priorto testing in the pylorus ligated rat model.

The pylorus ligated rat model used is a modification of the proceduredeveloped by Shay (Shay, H., Komarov, A. A. and Greenstein, M.: "Effectsof vagotomy in the rat." Arch. Surg. 49:210-226, 1949). MaleSprague-Dawley rats weighing approximately 200 g were starved 24 hoursprior to using, with water allowed ad libitum. Under light etheranesthetic the pylorus is ligated, simultaneously the rat is dosedintraperitoneally (i.p.) or subcutaneously (s.c.) and allowed 2 hoursfor stomach acid accumulation. At the end of 2 hours the rats aresacrificed. Stomach content is measured and titrated to a pH end pointof 7.0. Each experiment has its own control group for determiningpercent of acid change over the 2-hour time period.

Specific compounds within the scope of the above general classes ofdirect acting 5-HT1A agonists were tested. For evaluation purposes, thecompound to be tested is dissolved in distilled water, or in 10%dimethyl sulfoxide, depending upon its solubility. The results of theseevaluations are set forth below in Tables I through VI. All compoundswere dosed intraperitoneally, unless otherwise indicated.

                  TABLE I                                                         ______________________________________                                         ##STR29##                                                                    Evaluation       R                                                            Example          and    Dose    Percent                                       No.     X.sup.4  R.sup.1                                                                              μmoles/kg                                                                          Inhibition                                    ______________________________________                                        1       OMe      Pr     10      96.4 ± 0.7                                 2       SMe      Pr     10      94.9 ± 1.2 (+) isomer                      3       SMe      Pr     10      89.8 ± 4.9 (-) isomer                      4       CONH.sub.2                                                                             Pr     10      82.5 ± 7.4                                 5       SMe      Me     10      80.7 ± 8.4                                 6       Br       Pr     10      39.6 ± 10.9                                7       F        Pr     10      24.6 ± 7.9                                 8       OH       Pr     2.0     80.1 ± 6.3                                 ______________________________________                                    

                  TABLE II                                                        ______________________________________                                         ##STR30##                                                                    Evaluation                                                                    Example          R.sup.4 and  Dose    Percent                                 No.     X.sup.1  R.sup.5 Y.sup.1                                                                            μmoles/kg                                                                          Inhibition                              ______________________________________                                        9       CN       Pr      H    10      92.2 ± 3.2                           10      CN       Me      H    10      91.6 ± 3.9                           11      NO.sub.2 Pr      H    10      89.8 ± 1.4                           12      Br       Pr      H    10      87.0 ± 1.8                           13      CO.sub.2 Me                                                                            Pr      H    2.0     86.4 ± 2.5                           14      OMe      Pr      H    10      86.4 ± 4.0                           15      CO.sub.2 H                                                                             Pr      H    10      81.7 ± 5.8                           16      OMe      Pr      iPr  10      80.9 ± 5.5                           17      CHO      Me      H    2.0     79.2 ± 4.6                           18      CONH.sub.2                                                                             Pr      H    10      65.5 ± 7.1                           ______________________________________                                    

                  TABLE III                                                       ______________________________________                                         ##STR31##                                                                    Evaluation                                                                    Example                    Dose     Percent                                   No.      X.sup.5   R.sup.14                                                                              μmoles/kg                                                                           Inhibition                                ______________________________________                                        19       CONH.sub.2                                                                              Pr      10       92.7 ± 3.3                             ______________________________________                                    

                                      TABLE IV                                    __________________________________________________________________________     ##STR32##                                                                    Evaluation               Dose  Percent                                        Example No.                                                                          R.sup.12                                                                            Z           μmoles/kg                                                                        Inhibition                                     __________________________________________________________________________    20     cyclopentyl                                                                          ##STR33##  10    72.4 ± 7.5                                  21     cyclopentyl                                                                         cyclooctyl  10    65.1 ± 5.7                                  22     cyclohexyl                                                                          C(CH.sub.3).sub.3                                                                         10    30.8 ± 12.3                                 23     cyclopentyl                                                                         C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                              10    26.4 ± 15.4                                 24     cyclopentyl                                                                         cyclopentyl 10    19.7 ± 14.8                                 __________________________________________________________________________

                                      TABLE V                                     __________________________________________________________________________     ##STR34##                                                                    Evaluation                                                                    Example                     Dose  Percent                                     No.   X.sup.6                                                                          R.sup.16        R.sup.15                                                                         μmoles/kg                                                                        Inhibition                                  __________________________________________________________________________    25    OH (CH.sub.2).sub.3 -cyclohexyl                                                                  H  10    70.4 ± 8.4                               26    H                                                                                 ##STR35##      H  10    58.9 ± 6.6                               27    OEt                                                                              (CH.sub.2).sub.2C.sub.6 H.sub.5                                                               H  10    38.3 ± 15.9                              28    H                                                                                 ##STR36##         10    29.3 ± 10.0 (-) isomer                   29    H                                                                                 ##STR37##         10    24.6 ± 9.2 (+) isomer                    30    H  (CH.sub.2).sub.2C.sub.6 H.sub.5                                                               H  10    0.3 ± 14.1                               __________________________________________________________________________

                  TABLE VI                                                        ______________________________________                                         ##STR38##                                                                    Evaluation                                                                    Example                                                                       No.       X        Y       μmoles/kg                                                                          Inhibition                                 ______________________________________                                        31        H        OH      10      48.2 ± 17.5                             32        OH       H       10      22.6 ± 11.8                             ______________________________________                                    

As a standard serotonin (5-HT) was also evaluated in the pylorus ligatedrat model. At a dose of 20 micromoles/kg, 5-HT demonstrated 56.1percent, plus or minus 9.7, inhibition of gastric acid secretion.

The ED₅₀ values for certain specific compounds were estimated based ondata from the pylorus ligated rat model evaluations. These results areset forth below in Table VII. Under "Dose", i.p. means intraperitoneallyand s.c. means subcutaneously.

                  TABLE VII                                                       ______________________________________                                        Evaluation                                                                    Example                ED.sub.50                                              No.             Dose   μmoles/kg                                           ______________________________________                                        1               i.p.   1.54                                                   2               i.p.   1.56                                                   3               i.p.   1.42                                                   8               i.p.   1.56                                                   8               s.c.   0.46                                                   13              i.p.   <0.10                                                  14              i.p.   <0.10                                                  15              i.p.   1.00                                                   17              i.p.   1.26                                                   33              s.c.   4.19                                                   (buspirone)                                                                   Standard        i.p.   11.50                                                  (5-HT)                                                                        ______________________________________                                    

We claim:
 1. A method of inhibiting gastric acid secretion in mammals inneed of gastric acid secretion inhibition comprising administering tosaid mammal a pharmaceutically effective dose of a direct acting5-HT_(1A) agonist which is a 5-substituted-3-aminochromane or apharmaceutically acceptable acid addition salt thereof.
 2. The methodaccording to claim 1 wherein said mammals are humans.
 3. The methodaccording to claim 2 wherein said 5-substituted-3-aminochromane has theformula ##STR39## where R is C₁ -C₄ alkyl, allyl, or cyclopropylmethyl;R¹ is hydrogen, C₁ -C₄ alkyl, allyl, or cyclopropylmethyl, or aryl(C₁-C₄ -alkyl);R² is hydrogen or methyl; X is --O--; R³ is C₁ -C₈ alkyl,aryl, substituted aryl, aryl(C₁ -C₄ -alkyl), substituted aryl(C₁ -C₄alkyl), or C₅ -C₇ cycloalkyl; n is 0, 1, or 2;and pharmaceuticallyacceptable acid addition salts thereof.
 4. The method according to claim3 wherein said 5-substituted-3-aminochromane is 3-(di-n-propylamino)-5-methylthiochromane or a pharmaceutically acceptableacid addition salt thereof.